Pollock, Bruce E.

Background Pediatric pituitary adenoma is a rare skull base neoplasm, accounting for 3% of all intracranial neoplasms in children and 5% of pituitary adenomas. Compared with pituitary tumors in adults, secreting tumors predominate and longer disease trajectories are expected due to the patient age resulting in a natural history and treatment paradigm that is complex and controversial. Objectives The aims of this study were to describe a large, single-institution series of pediatric pituitary adenomas with extensive long-term follow-up and to conduct a systematic review examining outcomes after pituitary adenoma surgery in the pediatric population. Methods The study cohort was compiled by searching institutional pathology and operative reports using diagnosis and site codes for pituitary and sellar pathology, from 1956 to 2016. Systematic review of the English language literature since 1970 was conducted using PubMed, MEDLINE, Embase, and Google Scholar. Results Thirty-nine surgically managed pediatric pituitary adenomas were identified, including 15 prolactinomas, 14 corticotrophs, 7 somatotrophs, and 4 non-secreting adenomas. All patients underwent transsphenoidal resection (TSR) as the initial surgical treatment. Surgical cure was achieved in 18 (46%); 21 experienced recurrent/persistent disease, with secondary treatments including repeat surgery in 10, radiation in 14, adjuvant pharmacotherapy in 11, and bilateral adrenalectomy in 3. At the last follow-up (median 87 months, range 3–581), nine remained with recurrent/persistent disease (23%).Thirty-seven publications reporting surgical series of pediatric pituitary adenomas were included, containing 1,284 patients. Adrenocorticotropic hormone (ACTH)-secreting tumors were most prevalent (43%), followed by prolactin (PRL)-secreting (37%), growth hormone (GH)-secreting (12%), and nonsecreting (7%). Surgical cure was reported in 65%. Complications included pituitary insufficiency (23%), permanent visual dysfunction (6%), chronic diabetes insipidus (DI) (3%), and postoperative cerebrospinal fluid (CSF) leak (4%). Mean follow-up was 63 months (range 0–240), with recurrent/persistent disease reported in 18% at the time of last follow-up. Conclusion Pediatric pituitary adenomas are diverse and challenging tumors with complexities far beyond those encountered in the management of routine adult pituitary disease, including nuanced decision-making, a technically demanding operative environment, high propensity for recurrence, and the potentially serious consequences of hypopituitarism with respect to fertility and growth potential in a pediatric population. Optimal treatment requires a high degree of individualization, and patients are most likely to benefit from consolidated, multidisciplinary care in highly experienced centers.

Abstract BACKGROUND Stereotactic radiosurgery (SRS) is a commonly performed procedure for patients with intracranial meningiomas. OBJECTIVE To describe the clinical features of patients with radiation-induced cavernous malformations (RICM) after single-fraction meningioma SRS. METHODS Retrospective study of patients having single-fraction SRS for intracranial meningioma at our center from 1990 through 2009, and 1 patient who had single-fraction SRS elsewhere. Patients were excluded if they refused research authorization (n = 7), had a World Health Organization Grade II or III meningioma (n = 65), had a genetic predisposition for tumor development (n = 52), had prior or concurrent radiation therapy (n = 49), or had less than 2 yr of magnetic resonance imaging follow-up after SRS (n = 77). The median follow-up of the remaining 426 patients was 7.9 yr (range, 2-24.9). RESULTS Three RICM (0.7%) were identified at 2, 10, and 21 yr after SRS. Two patients were asymptomatic, whereas 1 patient had a brainstem hemorrhage causing facial weakness and numbness. The risk of developing an RICM after SRS was 0.2% at 5 yr and 0.9% at 15 yr. All patients were observed and remained stable without additional bleeding in follow-up of 7, 12.8, and 2 yr, respectively. A fourth patient developed progressive neurological dysfunction starting 7 yr after SRS at another center and was treated for several years with bevacizumab without improvement. Surgical resection was performed 11.5 yr after SRS and histologic examination was consistent with an RICM. CONCLUSION The risk of RICM after single-fraction SRS for intracranial meningiomas is very low, but the latency period noted until their detection emphasizes the need for extended imaging follow-up after SRS of benign lesions.

Objective: To describe audiometric outcomes following stereotactic radiosurgery (SRS) for jugular paraganglioma (JP). Study Design: Retrospective review. Setting: Tertiary referral center. Patients: Patients with pretreatment serviceable hearing (American Academy of Otolaryngology—Head and Neck Surgery [AAO-HNS] Class A or B) and serial post-SRS audiometric follow-up who underwent Gamma Knife SRS for JP between 1990 and 2017. Intervention(s): Gamma Knife SRS. Main Outcome Measures: Progression to nonserviceable hearing; correlation between baseline hearing and treatment parameters with audiometric outcomes. Results: Of 85 patients with JP who underwent SRS during the study period, 35 (66% female, median age 53) had pretreatment serviceable hearing and serial post-treatment audiometry available for review. Median tumor volume at the time of treatment was 7,080 mm3, median cochlear point dose was 5.8 Gy (interquartile range [IQR] 4.1 to 7.3 Gy), and median marginal and maximum tumor doses were 16 and 32 Gy, respectively. After a median follow-up of 37 months (IQR 16 to 77 mo), the median change in pure-tone average and speech discrimination score in the treated ear was −1.2 dB HL/yr (IQR −4.5 to 0.3) and 0%/yr (IQR 0–3.5%), compared with 0.07 dB HL/yr (IQR −0.03 to 0.12) and 0 %/yr (IQR 0 to 0%) in the contralateral untreated ear. Seven patients developed nonserviceable hearing (AAO-HNS Class C or D) at a median of 13.2 months following SRS (IQR 4.8 to 24 mo). Among those who maintained serviceable hearing, median audiometric follow-up was 42 months (IQR 18 to 77 mo). The Kaplan–Meier estimated rates of serviceable hearing at 1, 3, and 5 years following SRS were 91%, 80%, and 80%, respectively. Sixty percent of patients with pulsatile tinnitus who underwent SRS experienced varying levels of symptomatic improvement following treatment. Conclusion: The short- and intermediate-term risk of progression to nonserviceable hearing following SRS for JP is low. Data regarding the impact of cochlear dose from the vestibular schwannoma literature should not be freely applied to JP, since the impact of SRS parameters on hearing preservation seems to be less significant.

Abstract BACKGROUND When clinical presentation, laboratory studies, or imaging cannot diagnose cavernous sinus (CS) and/or Meckel's cave (MC) lesions, biopsy may be necessary. OBJECTIVE To review our institutional series of biopsies of indeterminate CS and MC lesions. METHODS Records from January 1994 to June 2016 were searched for biopsied indeterminate CS and MC lesions. We defined indeterminate as having an atypical imaging appearance or a broad differential and the need for tissue for definitive diagnosis. We defined primary tumors as originating from cells inherent or near the CS and MC. RESULTS Eighty-five patients were included (median age 59 [2-85] yr); 22 (28%) had a cancer history. Approaches included frontotemporal craniotomy (n = 48, 56%), endoscopic endonasal (n = 20, 24%), percutaneous transforamen ovale (n = 12, 14%), or retrosigmoid craniotomy (n = 5, 6%). Final diagnosis was metastatic in 27 (32%), primary in 21 (25%), inflammatory in 13 (15%), hematologic in 11 (13%), fungal in 5 (5%), and nondefinitive or nondiagnostic in 8 (10%) patients. Thirteen (59%) patients with a cancer history (n = 22) had a diagnosis consistent with their prior cancer; the remaining had a second pathology (n = 6, 27%) or nondiagnostic biopsy (n = 3, 14%). Two patients had surgical complications resulting in death. CONCLUSION In this patient cohort, metastatic tumors were the most likely pathology. The biopsy threshold should be lower in patients with a cancer history if clinical or radiographic diagnosis is uncertain as 27% had a second disease. However, we consider biopsy as a last resort because the risk of major morbidity/mortality, while low, is not zero.

LBA4 Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. Methods: Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. Results: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs. 2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5% with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001). Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR = 1.02, p = 0.93). Conclusions: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS. Clinical trial information: NCT00377156.

Abstract BACKGROUND: Radiation-based treatment options of large intracranial arteriovenous malformations (AVM) must balance the likelihood of obliteration with the risk of adverse radiation effects (ARE). OBJECTIVE: To analyze the efficacy and risks of volume-staged stereotactic radiosurgery (VS-SRS) for AVM. METHODS: Retrospective study of 34 AVM patients having VS-SRS between 1997 and 2012. A median of 2 stages (range, 2-4) was used to treat a median AVM volume of 22.2 cm 3 (range, 7.4-56.7). The median AVM margin dose was 16 Gy (range, 14-18); the median radiosurgery-based AVM score was 2.81 (range, 1.54-6.45). The median follow-up after VS-SRS was 8.2 years (range, 3-13.3). RESULTS: Nidus obliteration was noted in 18 patients (53%) after VS-SRS. The rate of obliteration was 14% at 3 years, 54% at 5 years, and 75% at 7 years. Six patients (18%) had 11 bleeds after VS-SRS. Two patients (6%) remained neurologically stable, 2 (6%) patients had significant deficits, and 2 patients (6%) died. The actuarial risk of a first bleed after VS-SRS was 6% at 1 year, 12% at 3 years, and 19% at 7 years. Six patients (18%) underwent repeat SRS; all achieved nidus obliteration for an overall cure rate of 71%. Two patients (6%) had a permanent ARE after VS-SRS or repeat SRS. CONCLUSION: VS-SRS permitted large volume intracranial AVM to be treated with a low rate of ARE. Further study is needed on dose escalation and decreasing the treatment volume per stage to determine if this will increase the rate of obliteration with this technique.

Abstract BACKGROUND Late adverse radiation effects (ARE) typically occur many years after stereotactic radiosurgery (SRS) of intracranial arteriovenous malformations (AVM). They are characterized by perilesional edema or cyst formation and are distinct from radiation-induced changes (RIC) noted in the first 1 to 2 years after AVM SRS and radiation necrosis. OBJECTIVE To determine the incidence of late ARE after AVM SRS. METHODS Retrospective review of 233 AVM patients having SRS from 1990 to 2009. Patients had sporadic AVM, no prior radiation, and a minimum of 5 years of magnetic resonance imaging (MRI) follow-up. The median MRI follow-up after SRS was 9.8 years (range, 5-24.2). RESULTS Late ARE were observed in 16 patients (6.9%) at a median of 8.7 years after SRS (range, 2.0-16.1). The 5-, 10-, and 15-year incidence of late ARE was 0.4%, 7.7%, and 12.5%, respectively. Eight patients (3.4%) were symptomatic at the time of ARE detection. Three of 8 patients who were initially asymptomatic had documented cyst progression (at 11, 40, and 42 months), for an overall symptomatic rate of 4.7%. Five patients with asymptomatic ARE have been observed for a median of 9.3 years (range, 2.0-14.1) without progression. Patients having early RIC (hazard ratio [HR] = 2.11, P < .001), patients having obliteration (HR = 1.24, P = .02), and patients having SRS before April 1997 (HR = 1.12, P = .02) were more likely to develop late ARE. CONCLUSION Late ARE are common in AVM patients who develop early RIC after SRS. Resection of the thrombosed AVM and the adjacent damaged tissue is effective at eliminating the mass effect and improving patients’ neurological condition.

OBJECTIVENelson-Salassa syndrome (NSS) is a rare consequence of bilateral adrenalectomy (ADX) for refractory hypercortisolism due to Cushing disease (CD). Although classically defined by rapid growth of a large, invasive, adrenocorticotropin hormone (ACTH)–secreting pituitary tumor after bilateral ADX that causes cutaneous hyperpigmentation, visual disturbance, and high levels of ACTH, clinical experience suggests more variability.METHODSThe authors conducted a retrospective chart review of all patients 18 years and older with a history of bilateral ADX for CD, adequate pituitary MRI, and at least 2 years of clinical follow-up. Statistical tests included Student's t-test, chi-square test, Fisher's exact test, multivariate analysis, and derived receiver operating characteristic curves.RESULTSBetween 1956 and 2015, 302 patients underwent bilateral ADX for the treatment of hypercortisolism caused by CD; 88 had requisite imaging and follow-up (mean 16 years). Forty-seven patients (53%) had radiographic progression of pituitary disease and were diagnosed with NSS. Compared with patients who did not experience progression, those who developed NSS were significantly younger at the time of CD diagnosis (33 vs 44 years, p = 0.007) and at the time of bilateral ADX (35 vs 49 years, p = 0.007), had larger tumors at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03), and were more likely to have undergone external-beam radiation therapy (EBRT, 43% vs 12%, p = 0.005). Among NSS patients, the mean tumor growth was 7 mm/yr (SE 6 mm/yr); the median tumor growth was 3 mm/yr. Prevalence of pathognomonic symptoms was low; the classic triad occurred in 9%, while hyperpigmentation without visual field deficit was observed in 23%, and 68% remained asymptomatic despite radiographic disease progression. NSS required treatment in 14 patients (30%).CONCLUSIONSNSS is a prevalent sequela of CD after bilateral ADX and affects more than 50% of patients. However, although radiological evidence of NSS is common, it is most often clinically indolent, with only a small minority of patients developing the more aggressive disease phenotype characterized by clinically meaningful symptoms and indications for treatment. Young age at the time of CD diagnosis or treatment with bilateral ADX, large tumor size at CD diagnosis, and EBRT are associated with progression to NSS and may be markers of aggressiveness.