International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Silent Corticotroph Adenomas After Stereotactic Radiosurgery: A CaseeControl Study Zhiyuan Xu, MD,* Scott Ellis, BS,* Cheng-Chia Lee, MD,* Robert M. Starke, MD,* David Schlesinger, PhD,*,y Mary Lee Vance, MD,*,z M. Beatriz Lopes, MD, PhD,x and Jason Sheehan, MD, PhD*,y Departments of *Neurological Surgery, yRadiation Oncology, and zInternal Medicine and xDivision of Neuropathology, University of Virginia, Charlottesville, Virginia Received May 8, 2014, and in revised form Jul 7, 2014. Accepted for publication Jul 11, 2014.
Summary Outcomes of SRS for silent corticotroph adenoma (SCA) with a reportedly high recurrence rate have not been reported yet. We reviewed 34 consecutive SCA patients and 70 comparable other subtypes of nonfunctioning pituitary adenoma (NFA) patients treated with SRS at our institution. Compared with other NFAs, SCAs exhibited a higher progression rate. SRS is an important adjuvant treatment for control of tumor growth. Increased margin radiation dose seems necessary to achieve tumor control in SCA patients.
Purpose: To investigate the safety and effectiveness of stereotactic radiosurgery (SRS) in patients with a silent corticotroph adenoma (SCA) compared with patients with other subtypes of noneadrenocorticotropic hormone staining nonfunctioning pituitary adenoma (NFA). Methods and Materials: The clinical features and outcomes of 104 NFA patients treated with SRS in our center between September 1994 and August 2012 were evaluated. Among them, 34 consecutive patients with a confirmatory SCA were identified. A control group of 70 patients with other subtypes of NFA were selected for review based on comparable baseline features, including sex, age at the time of SRS, tumor size, margin radiation dose to the tumor, and duration of follow-up. Results: The median follow-up after SRS was 56 months (range, 6-200 months). No patients with an SCA developed Cushing disease during the follow-up. Tumor control was achieved in 21 of 34 patients (62%) in the SCA group, compared with 65 of 70 patients (93%) in the NFA group. The median progression-free survival (PFS) was 58 months in the SCA group. The actuarial PFS was 73%, 46%, and 31% in the SCA group and was 94%, 87%, and 87% in the NFA group at 3, 5, and 8 years, respectively. Silent corticotroph adenomas treated with a dose of 17 Gy exhibited improved PFS. New-onset loss of pituitary function developed in 10 patients (29%) in the SCA group, whereas it occurred in 18 patients (26%) in the NFA group. Eight patients (24%) in the SCA group experienced worsening of a visual field deficit or visual acuity attributed to the tumor progression, as did 6 patients (9%) in the NFA group. Conclusion: Silent corticotroph adenomas exhibited a more aggressive course with a higher progression rate than other subtypes of NFAs. Stereotactic radiosurgery is an important adjuvant treatment for control of tumor growth. Increased radiation dose may lead to improved tumor control in SCA patients. Ó 2014 Elsevier Inc.
Reprint requests to: Jason Sheehan, MD, PhD, Department of Neurological Surgery, 1215 Lee Street, University of Virginia, Charlottesville, VA 22908. Tel: (434) 924-8129; E-mail:
[email protected] Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e8, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.07.013
Conflict of interest: D.S. received a grant from Elekta for a study of the impact of onyx on the dose of Gamma Knife radiosurgery.
2
Xu et al.
Introduction The silent corticotroph adenoma (SCA) represents an uncommon subset of nonfunctioning pituitary adenomas (NFAs). It was first reported by Kovacs et al (1) in 1978 and further defined by Horvath et al (2) in 1980. This subpopulation of NFA is characterized by a lack of hypercortisolemia, no clinical evidence of Cushing disease (CD), and positive immunostaining for adrenocorticotropic hormone (ACTH). It accounted for 9% in a patient series of both functioning pituitary adenomas and NFAs (3). The recurrence of or progression of residual tumor in patients with an NFA after microsurgical resection varies, depending upon the extent of resection. A recurrence rate of 10% to 25% was reported in patients in whom a gross total resection was achieved, whereas it was as high as 50% in patients who underwent a subtotal resection (4-6). Historically, SCA is considered an aggressive tumor characterized by a biologic behavior between that of (ACTH-negative) NFA and adenomas causing CD (7-14), although contradicting evidence does exist (9,15,16). The current knowledge of the natural history and clinical characteristics of this disease is based on a small number of studies of patients undergoing surgical resection (7,9-12,16,17). Stereotactic radiosurgery (SRS) has been used for recurrent or enlarging adenomas in patients who fail surgical interventions (18). However, no study to date has evaluated the clinical outcomes of SCA patients after SRS; thus, efficacy remains unknown. In this series we investigate this distinct group of patients so as to shed light on the safety and effectiveness of SRS in patients with an SCA compared with patients with other subtypes of non-ACTH staining NFA.
Methods and Materials Patient population A total of 170 NFA patients were treated with SRS in the Gamma Knife Center at the University of Virginia between September 1994 and October 2011. This study was a retrospective review of the prospectively maintained, institutional review boardeapproved, database regarding all patient characteristics, outcomes, and radiosurgical parameters. Among them, 34 consecutive patients (20%) with an SCA were identified according to histopathologic evaluation of the previously resected adenoma. The diagnosis of SCA was made on the basis of the lack of the clinical and biochemical manifestations of CD, positive immunoreactivity for ACTH according to the pathology report, and negative endocrine studies regarding Cushing disease before SRS. The control NFA group consisted of 70 patients with adequate histopathologic data to confirm the diagnosis of a non-ACTH staining NFA subtype, including gonadotroph adenomas (with immunoreactivity for the gonadotropin hormones b-follicle-stimulating hormone, b-luteinizing hormone, and/or a-subunit), silent growth hormone (GH) adenomas (with immunoreactivity for GH), or
International Journal of Radiation Oncology Biology Physics
null-cell adenomas (with lack of any immunoreactivity for pituitary hormones). The 2 groups had comparable baseline parameters, including age at the time of SRS, gender, prior surgical interventions, preceding visual field defect, cavernous sinus invasion at the time of SRS, margin radiation dose, and duration of follow-up. Twenty-one male (62%) and 13 female patients (38%) with a median age of 52.5 years constituted the SCA group, whereas 70 patients including 46 male (66%) and 24 female (34%) meeting the previously described criteria constituted the NFA control group. The median follow-up after SRS in the entire series was 56 months (range, 6-200 months). Demographic, clinical, hormonal, and imaging characteristics and the clinical parameters for all pituitary adenoma patients are displayed in Table 1. None of the patients in the study had clinical or biochemical manifestation of hypercortisolism. Before SRS all patients underwent at least one transsphenoidal tumor resection (range, 1-3 operations) (Table 1). Patients received a neuro-ophthalmologic evaluation and comprehensive endocrine studies, which included serum cortisol, ACTH, free thyroxine, thyroid-stimulating hormone (TSH), insulin-like growth factor 1 (IGF-1), GH, and testosterone (men) immediately before SRS. Visual field defects were detected in 18 patients (53%) before SRS in the SCA group and in 32 patients (46%) in the NFA group (c2 test, PZ.54). Panhypopituitarism was present in 5 patients prior to SRS in the SCA group and in 9 patients in the NFA group (Fisher exact test, PZ.77). There were 10 patients (29%) in the SCA group and 18 patients (26%) in the NFA group who underwent a subtotal tumor resection followed by adjuvant radiosurgery (c2 test, PZ.69).
Radiosurgical technique Stereotactic radiosurgery for pituitary adenomas has been described previously. Stereotactic radiosurgery was performed using the Leksell Gamma Knife (Elekta, Stockholm, Sweden) model U between 1990 and 2001, model C from 2001 to 2007, and then replaced by the model Perfexion thereafter. In brief, the Gamma frame placement was performed under monitored sedation in the operating room to minimize any patient discomfort. After the frame placement, volumetric T1-weighted MRI sequences were obtained with and without the administration of gadolinium in all patients. Images were reconstructed into axial and coronal series with contiguous 1.2-mm-thick slices. Fat suppression imaging was obtained through the region just posterior of the orbits to a region just anterior of the pons. Leksell GammaPlan (version 3-10.1; Elekta) treatment planning software was used for SRS dose planning based on the stereotactic MRI for all patients. The selection of dose to the pituitary adenoma was determined generally according to the status of the adjacent cranial nerve function, previous radiation therapy (RT), adenoma volume, and the distance between the adenoma and adjacent critical structures, in particular the optic apparatus. Typically, the dose to the optic apparatus was kept below 8 Gy to any volume of the apparatus greater than
Volume - Number - 2014 Table 1 GKS
Silent corticotroph adenomas after SRS
Baseline characteristics of 104 patients treated with
Characteristic
n
Total Sex Male Female Age at GKS (y) Median Range Prior TSA (n) 1 2 3 Prior RT Prior craniotomy and tumor resection 0 1 2 Indication for GKS Upfront postoperative adjuvant At the time of tumor recurrence Indeterminate Visual field defect before GKS Adenoma subtype Gonadotroph Null cell Silent GH Cavernous sinus invasion Follow-up after GKS (mo) Median Range
104
%
SCA
NFA*
n
n
%
%
Py
34 33 70 67 .69
67 64 21 62 46 66 37 36 13 38 24 34 .54 50.5 19-82
52.5 20-82
50.5 19-76 .84
42 40 15 44 27 39 48 46 15 44 33 47 14 13 4 12 10 14 3 3 3 11 0
.033 .37
93 89 29 85 64 91 8 8 3 9 5 7 3 3 2 6 1 1
then on. Tumor volume was determined with a volume analysis approach, which was described by Snell et al (19). Tumor volume on MRI at the time of SRS was used as the reference data. Tumor progression was defined as an increase in tumor volume of 15% relative to the baseline tumor volume. Tumor decrease was defined as a decrease of the tumor volume by 15% of the pretreatment volume. Tumor stability was defined as a tumor that had a volume change of
