Lactotroph adenoma radiosurgery

Lactotroph adenoma radiosurgery

Lactotroph adenoma radiosurgery also serves as an option for those refractory to medical and surgical therapy 1).

GKRS plays a significant role in the treatment of non-functioning [NFA] and hormonal-active [HAA] pituitary adenoma. It affords high rate of tumor control and offers low risk of collateral neurological or endocrine axis injury. A study showed that control of tumor growth was achieved in 90% patients, shrinkage of tumor in 54% and arrest of progression in 36% cases after GKRS treatment. The biochemical remission rate in GH secreting adenoma was 57%, ACTH adenoma was 67% and prolactinoma was 40%. Age less than 50 years and tumor volume less than 5cm3 were associated with a favourable radiosurgical outcome 2).

Case series

retrospective study included lactotroph adenoma treated with SRS between 1997 and 2016 at ten institutions. Patients’ clinical and treatment parameters were investigated. Patients were considered to be in endocrine remission when they had a normal level of prolactin (PRL) without requiring dopamine agonist medications. Endocrine control was defined as endocrine remission or a controlled PRL level ≤ 30 ng/ml with dopamine agonist therapy. Other outcomes were evaluated including new-onset hormone deficiency, tumor recurrence, and new neurological complications.

The study cohort comprised 289 patients. The endocrine remission rates were 28%, 41%, and 54% at 3, 5, and 8 years after SRS, respectively. Following SRS, 25% of patients (72/289) had new hormone deficiency. Sixty-three percent of the patients (127/201) with available data attained endocrine control. Three percent of patients (9/269) had a new visual complication after SRS. Five percent of the patients (13/285) were recorded as having tumor progression. A pretreatment PRL level ≤ 270 ng/ml was a predictor of endocrine remission (p = 0.005, adjusted HR 0.487). An increasing margin dose resulted in better endocrine control after SRS (p = 0.033, adjusted OR 1.087).

In patients with medically refractory prolactinomas or a residual/recurrent prolactinoma, SRS affords remarkable therapeutic effects in endocrine remission, endocrine control, and tumor control. New-onset hypopituitarism is the most common adverse event 3).

2015

Radiotherapy as an alternative and adjuvant treatment for prolactinomas has been performed at the Department of Radiation Oncology, Prince of Wales Cancer Centre, Sydney, New South Wales, Australia, with the linear accelerator since 1990.

In a retrospective review of 13 patients managed with stereotactic radiosurgery (SRS) and 5 managed with fractionated stereotactic radiotherapy (FSRT), as well as 5 managed with conventional radiotherapy, at the Prince of Wales Hospital. Patients with a histopathologically diagnosed prolactinoma were eligible. Those patients who had a confirmed pathological diagnosis of prolactinoma following surgical intervention, a prolactin level elevated above 500 μg/L, or a prolactin level persistently elevated above 200 μg/L with exclusion of other causes were represented in this review.

At the end of documented follow-up (SRS median 6 years, FSRT median 2 years), no SRS patients showed an increase in tumour volume. After FSRT, 1 patient showed an increase in size, 2 showed a decrease in size and 2 patients showed no change. Prolactin levels trended towards improvement after SRS and FSRT, but no patients achieved the remission level of <20 μg/L. Seven of 13 patients in the SRS group achieved a level of <500 μg/L, whereas no patients reached this target after FSRT.

A reduction in prolactin level is frequent after SRS and FSRT for prolactinomas; however, true biochemical remission is uncommon. Tumour volume control in this series was excellent, but this may be related to the natural history of the disease. Morbidity and mortality after stereotactic radiation were very low in this series 4).


Cohen-Inbar et al., reviewed the outcome of patients with medically and surgically refractory prolactinomas treated with Gamma Knife radiosurgery (GKRS) during a 22 years follow-up period.

They reviewed the patient database at the University of Virginia Gamma Knife center during a 25-year period (1989-2014), identifying 38 patients having neurosurgical, radiological and endocrine follow-up.

Median age at GKRS treatment was 43 years. Median follow-up was 42.3 months (range 6-207.9). 55.3 % (n = 21) were taking a dopamine agonist at time of GKRS. 63.2 % (n = 24) had cavernous sinus tumor invasion. Endocrine remission (normal serum prolactin off of a dopamine agonist) was achieved in 50 % (n = 19). GKRS induced hypopituitarism occurred in 30.3 % (n = 10). Cavernous sinus involvement was shown to be a significant negative prognosticator of endocrine remission. Taking a dopamine agonist drug at the time of GKRS showed a tendency to decrease the probability for endocrine remission.

GKRS for refractory prolactinomas can lead to endocrine remission in many patients. Hypopituitarism is the most common side effect of GKRS 5).

2013

evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm3 (range 0.3–11.6). The marginal tumor dose (median= 15 Gy, range 12–25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12–185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined asa decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six(27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy 6).

2006

Twenty-three patients were included in analysis of endocrine outcomes (median and average follow-up of 55 and 58 mo, respectively) and 28 patients were included in analysis of imaging outcomes (median and average follow-up of 48 and 52 mo, respectively). Twenty-six percent of patients achieved a normal serum prolactin (remission) with an average time of 24.5 months. Remission was significantly associated with being off of a dopamine agonist at the time of GKRS and a tumor volume less than 3.0 cm3 (P < 0.05 for both). Long-term image-based volumetric control was achieved in 89% of patients. Complications included new pituitary hormone deficiencies in 28% of patients and cranial nerve palsy in two patients (7%).

Clinical remission in 26% of treated patients is a modest result. However, because the GKRS treated tumors were refractory to other therapies and because complication rates were low, GKRS should be part of the armamentarium for treating refractory prolactinomas. Patients with tumors smaller than 3.0 cm3 and who are not receiving dopamine agonist at the time of treatment will likely benefit most 7).

2000

Twenty patients with prolactinomas were followed after GKS. Five patients were treated successfully; their prolactin (PRL) levels dropped into the normal range and dopaminergic drugs could be discontinued. Two spontaneous pregnancies were observed and 11 patients experienced improvement. Improvement was defined as normal PRL levels with the continued possibility of reduced medical treatment or a substantially reduced medical treatment dose with some degree of hyperprolactinemia maintained. The treatment failed in three patients who experienced no improvement. Patients treated with dopaminergic drugs during GKS did significantly less well in comparison with the untreated group when a cumulative distribution function (Kaplan-Meier estimate) was used. CONCLUSIONS:

The results of GKS for prolactinomas in this investigation are better than the results published by others. This may be an effect of case selection because there were no “salvage cases” in our group of patients. Because a dopamine agonist seemed to induce radioprotection in this series, it is suggested that GKS be performed during an intermission in drug therapy when the dopamine agonist is discontinued 8).

References

1)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
2)

Narayan V, Mohammed N, Bir SC, Savardekar AR, Patra DP, Bollam P, Nanda A. Long term Outcome of Non-functioning and Hormonal-active Pituitary Adenoma after Gamma Knife Radio Surgery. World Neurosurg. 2018 Mar 21. pii: S1878-8750(18)30576-X. doi: 10.1016/j.wneu.2018.03.094. [Epub ahead of print] PubMed PMID: 29574220.
3)

Hung YC, Lee CC, Yang HC, Mohammed N, Kearns KN, Nabeel AM, Abdel Karim K, Emad Eldin RM, El-Shehaby AMN, Reda WA, Tawadros SR, Liscak R, Jezkova J, Lunsford LD, Kano H, Sisterson ND, Martínez Álvarez R, Martínez Moreno NE, Kondziolka D, Golfinos JG, Grills I, Thompson A, Borghei-Razavi H, Maiti TK, Barnett GH, McInerney J, Zacharia BE, Xu Z, Sheehan JP. The benefit and risk of stereotactic radiosurgery for prolactinomas: an international multicenter cohort study. J Neurosurg. 2019 Aug 2:1-10. doi: 10.3171/2019.4.JNS183443. [Epub ahead of print] PubMed PMID: 31374549.
4)

Wilson PJ, Williams JR, Smee RI. Single-centre experience of stereotactic radiosurgery and fractionated stereotactic radiotherapy for prolactinomas with the linear accelerator. J Med Imaging Radiat Oncol. 2015 Jun;59(3):371-8. doi: 10.1111/1754-9485.12257. Epub 2014 Nov 20. PubMed PMID: 25410143.
5)

Cohen-Inbar O, Xu Z, Schlesinger D, Vance ML, Sheehan JP. Gamma Knife radiosurgery for medically and surgically refractory prolactinomas: long-term results. Pituitary. 2015 Dec;18(6):820-30. doi: 10.1007/s11102-015-0658-1. PubMed PMID: 25962347.
6)

Liu X, Kano H, Kondziolka D, Park KJ, Iyer A, Shin S, Niranjan A, Flickinger JC, Lunsford LD. Gamma knife stereotactic radiosurgery for drug resistant or intolerant invasive prolactinomas. Pituitary. 2013 Mar;16(1):68-75. PubMed PMID: 22302560.
7)

Pouratian N, Sheehan J, Jagannathan J, Laws ER Jr, Steiner L, Vance ML. Gamma knife radiosurgery for medically and surgically refractory prolactinomas. Neurosurgery. 2006 Aug;59(2):255-66; discussion 255-66. PubMed PMID: 16883166.
8)

Landolt AM, Lomax N. Gamma knife radiosurgery for prolactinomas. J Neurosurg. 2000 Dec;93 Suppl 3:14-8. PubMed PMID: 11143231.

Tentorial Angle

Tentorial Angle

Various techniques of measuring tentorial alignment and their surgical implications have been described; however, all of the methods are burdened with limitations and there is still a lack of consensus regarding the anatomical reference lines and cutoff values for tentorial angles to discriminate between “shallow” and “steep” angles 1) 2) 3).

Nemir et al., from the University Hospital Center ZagrebCroatia, present data on craniocaudal dimensions of posterior fossa cisterns, their relationship with tentorial alignment, and discuss their relevance in Supracerebellar Infratentorial approach and Occipital transtentorial approach

The clivustentorium (C-T) angle was measured to assess tentorial alignment. The following distances were used as craniocaudal cisternal measurements: quadrigeminal cistern = superior colliculus – inferior part of the splenium of corpus callosum (SC-ISCC), and superior cerebellar cistern = vermis – inferior part of the splenium of corpus callosum (VER-ISCC).

Median C-T angle value was 19 ± 7°, the quadrigeminal cistern height 6.7 ± 1.6 cm, and the superior cerebellar cistern height 10.4 ± 2.6 cm. The C-T angle was negatively correlated with the SC-ISCC distance (r = -0.271; p <  0.001) and the VER-ISCC distance (r = -0.052, p >  0.001). The SC-ISCC distance was positively correlated with the VER-ISCC distance (r = 0.282; p < 0.001) 4).


Studies have used the Twining line (from the tuberculum sellae to the torcula), or the floor of the fourth ventricle as reference lines and defined different cutoff values of “steepness”. The other important factors to be considered in approaching the pineal region are anatomic features of thequadrigeminal cistern and superior cerebellar cistern, as both host important neurovascular structures and serve as anatomic corridors 5) 6) 7) 8) 9).

The current trend to use the Twining line to define this angle has significant pitfalls.

The goal of a study of Syed et al., was to provide a new and accurate way to measure the tentorial angle and demonstrate its impact on surgeries of the pineal region.

n-angle to measure the tentorial angle was introduced using the floor of the fourth ventricle and the torcula. Comparisons with older techniques were made to illustrate reliability. Midline sagittal MR images were used to measure the tentorial angle in 240 individuals to obtain population-based data. A cohort of 8 patients who underwent either the infratentorial or the transtentorial approach to the pineal or upper vermian region were examined in search of correlations between tentorial angle and surgical approach.

The data in this study showed that the Twining line technique understates the tentorial angle in people with low-lying torcula. The n-angle is more reliable in reflecting the true steepness of the tentorium regardless of torcula position. On average, men have slightly steeper tentoriums. In the clinical cohort, all patients who underwent infratentorial surgery had tentorial angles <55°, whereas the majority of patients who underwent transtentorial surgeries had angles >67°.

The n-angle provides a reliable and accurate way to describe the slope of the tentorium. The population-based average of 60° may be a useful measurement to influence the choice of surgical approach, either under or through the tentorium, to the pineal region 10).


A steep tentorial angle is an unfavorable preoperative radiographic factor for achieving maximal resection with the supracerebellar infratentorial approach. Collectively, a study of Zhao et al. showed that versatility is required to treat patients with falcotentorial meningiomas and that treatment goals and surgical approach must be individualized to obtain optimal surgical results 11).

References

1) , 7) , 10)

Syed HR, Jean WC. A Novel Method to Measure the Tentorial Angle and the Implications on Surgeries of the Pineal Region. World Neurosurg. 2018 Mar;111:e213-e220. doi: 10.1016/j.wneu.2017.12.037. Epub 2017 Dec 16. PubMed PMID: 29258947.
2)

Pan Y, Wang C, Ding X, Lu Y. The Krause approach: MRI measurements in the Chinese population. J Clin Neurosci. 2011 Jun;18(6):794-7. doi: 10.1016/j.jocn.2010.10.017. Epub 2011 Apr 19. PubMed PMID: 21507648.
3)

Sade B, Lee JH. Significance of the tentorial alignment in approaching the trigeminal nerve and the ventral petrous region through the suboccipital retrosigmoid technique. J Neurosurg. 2007 Nov;107(5):932-6. PubMed PMID: 17977263.
4)

Nemir J, Njirić N, Ivanković D, Barl P, Domazet I, Radoš M, Mrak G, Paladino J. Tentorial alignment and its relationship to cisternal dimensions of the pineal region: MRI anatomical study with surgical implications using the new clivotentorial method. Clin Neurol Neurosurg. 2018 Jun 28;172:99-104. doi: 10.1016/j.clineuro.2018.06.028. [Epub ahead of print] PubMed PMID: 29986205.
5)

Rhoton AL Jr. Tentorial incisura. Neurosurgery. 2000 Sep;47(3 Suppl):S131-53. PubMed PMID: 10983307.
6)

Hart MG, Santarius T, Kirollos RW. How I do it–pineal surgery: supracerebellar infratentorial versus occipital transtentorial. Acta Neurochir (Wien). 2013 Mar;155(3):463-7. doi: 10.1007/s00701-012-1589-5. Epub 2012 Dec 27. PubMed PMID: 23269352.
8)

Gu Y, Hu F, Zhang X. Purely endoscopic resection of pineal region tumors using infratentorial supracerebellar approach: How I do it. Acta Neurochir (Wien). 2016 Nov;158(11):2155-2158. Epub 2016 Aug 9. PubMed PMID: 27506850.
9)

Qi S, Fan J, Zhang XA, Zhang H, Qiu B, Fang L. Radical resection of nongerminomatous pineal region tumors via the occipital transtentorial approach based on arachnoidal consideration: experience on a series of 143 patients. Acta Neurochir (Wien). 2014 Dec;156(12):2253-62. doi: 10.1007/s00701-014-2224-4. Epub 2014 Sep 23. Erratum in: Acta Neurochir (Wien). 2015 Feb;157(2):349. PubMed PMID: 25246142.
11)

Zhao X, Belykh E, Przybylowski CJ, Borba Moreira L, Gandhi S, Tayebi Meybodi A, Cavallo C, Valli D, Wicks RT, Nakaji P. Surgical treatment of falcotentorial meningiomas: a retrospective review of a single-institution experience. J Neurosurg. 2019 Aug 2:1-12. doi: 10.3171/2019.4.JNS19208. [Epub ahead of print] PubMed PMID: 31374550.
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