Epigenetic dysregulation in meningiomas.

Background: Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, tumors with benign histology may behave aggressively and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue. Methods: Whole-exome sequencing and methylation array profiling were performed on 12 dura/meningioma pairs (11 WHO grade I and 1 WHO grade II). Single-nucleotide polymorphism (SNP) genotyping and methylation array profiling were performed on an additional 19 meningiomas (9 WHO grade I, 5 WHO grade II, 4 WHO grade III). Results: Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower-grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increasing histopathologic grade. Conclusion: These findings support future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in meningioma formation as well as studies of the utility of polycomb inhibitors for the treatment of malignant meningiomas.

Calcified Prolactinoma of the Pituitary Gland: Illustrative Case Reports Highlighting Medical versus Surgical Intervention.

The presence of calcification is uncommon in pituitary adenomas, and often lends support to other diagnoses including craniopharyngioma. The majority of calcified pituitary adenomas are prolactin-secreting tumors. We report two patients with calcified macroprolactinomas, one that was treated medically with a biochemical response and partial tumor response, and one that was treated successfully via an endoscopic endonasal transsphenoidal approach. Suspected calcified prolactinomas can be initially managed medically as per standard treatment for typical prolactinomas; however, the presence of diffuse calcification may hinder tumor shrinkage. Tumors that are refractory to medical treatment can be safely managed with surgery.

Hemorrhagic Presentation of Rathke Cleft Cysts: A Surgical Case Series.

BACKGROUND: Rathke cleft cysts (RCCs) are benign sellar and suprasellar lesions commonly presenting as asymptomatic incidental findings. Rarely, RCCs hemorrhage and mimic pituitary apoplexy on presentation. OBJECTIVE: To review a series of hemorrhagic RCCs for physicians encountering this rare presentation. METHODS: A database review of >1700 transsphenoidal pituitary operations was performed at the USC Pituitary Center to identify patients with pathologically confirmed RCCs presenting with acute symptoms and evidence of hemorrhage at the time of surgery. Surgical treatment involved transsphenoidal RCC fenestration and drainage. Clinical, endocrine, and imaging outcomes were reviewed. RESULTS: A total of 119 RCCs were identified, and 6 (5.0%) presented with hemorrhage mimicking pituitary apoplexy. Presenting symptoms included acute onset headaches (5/6), vision loss (2/6), and oculomotor nerve palsy (n = 1). Endocrine disturbances at presentation included pre-existing amenorrhea in all female patients (3/3), hypothyroidism (n = 2), panhypopituitarism (n = 2), and one with profound hyponatremia (Na 116 meq/L). All patients underwent endonasal transsphenoidal fenestration and drainage with no major complications. Over mean follow-up of 38.4 mo, 2/2 patients with vision loss reported improvement, and 2/5 patients with headaches reported improvement. Although all women resumed menses, patients with preoperative hypopituitarism did not experience pituitary axis improvement. Follow-up magnetic resonance imaging showed no instances of RCC recurrence with a mean imaging follow-up of 38.6 mo. CONCLUSION: RCCs occasionally present with hemorrhage and clinical symptoms that may be confused with apoplexy. Outcomes following hemorrhagic RCC treatment are excellent when treated at tertiary pituitary centers. Although hyperprolactinemia often improves following surgery, other pituitary axis deficits typically do not.

Recurrent Rathke's Cleft Cysts: Incidence and Surgical Management in a Tertiary Pituitary Center over 2 Decades.

BACKGROUND: Limited data exist pertaining to outcomes following surgery for recurrent Rathke's cleft cysts (RCC). OBJECTIVE: To determine treatment outcomes in patients undergoing reoperation for recurrent or residual RCCs. METHODS: A retrospective analysis of 112 consecutive RCC operations in 109 patients between 1995 and 2017 was conducted. RESULTS: Eighteen patients underwent 21 RCC reoperations with a mean follow-up of 58 mo. Patient symptoms prior to reoperation included headaches (14, 66.7%) and vision loss (12, 57.1%). Thirteen of 18 patients (72.2%) required hormone supplementation prior to reoperation including 5 with diabetes insipidus (DI). Mean RCC diameter was 16 mm and 76% had suprasellar extension. Compared to index RCC cases, intraoperative cerebrospinal fluid leak repair was more common in reoperation cases (15/21, 71% vs 43/91, 47%, P = .05). There was 1 carotid artery injury without neurological sequelae, and 2 postoperative cerebrospinal fluid (CSF) leaks (9.5%). Rates of transient hyponatremia (3/10, 30% vs 4/91, 4.4%, P = .04) and transient DI (5/10, 50% vs 17/91, 18.7%, P = .04) were higher in the reoperation vs index group. Improved headaches and vision were reported in 4/12 (33%) and 8/12 (61.5%) of RCC reoperation patients, respectively. Two patients developed new permanent DI. A higher proportion of reoperation patients had RCC squamous metaplasia (24% vs 5.4%, P = .02) or wall inflammation (42.9% vs 2.2%, P < .001) on pathological examination. CONCLUSION: Reoperation for RCCs is generally safe at tertiary pituitary centers and often results in improved vision. Hypopituitarism is less likely to improve following reoperation for recurrent RCCs. Several histopathological features may help characterize "atypical RCCs" with a higher likelihood of recurrence/progression.

Complications associated with microscopic and endoscopic transsphenoidal pituitary surgery: experience of 1153 consecutive cases treated at a single tertiary care pituitary center.

OBJECTIVEPituitary adenomas (PAs) are benign neoplasms that are frequently encountered during workup for endocrinopathy, headache, or visual loss. Transsphenoidal surgery remains the first-line approach for PA resection. The authors retrospectively assessed complication rates associated with transsphenoidal PA resection from an institutional database.METHODSA retrospective analysis of 1153 consecutive transsphenoidal pituitary adenoma resections performed at the Keck Hospital of USC between November 1992 and March 2017 was conducted. Microscopic transsphenoidal resection was performed in 85.3% of cases, and endoscopic transsphenoidal resection was performed in 14.7%. Analysis of perioperative complications and patient and tumor risk factors was conducted.RESULTSThe overall median hospital stay was 3 days. There was 1 perioperative death (0.1%). Surgical complications included postoperative cerebrospinal fluid leak (2.6%), epistaxis (1.1%), postoperative hematoma (1.1%), meningitis (1.0%), cranial nerve paresis (0.8%), hydrocephalus (0.8%), vision loss (0.6%), stroke (0.3%), abdominal hematoma or infection (0.2%), carotid artery injury (0.1%), and vegetative state (0.2%). Perioperative medical complications included bacteremia/sepsis (0.5%), pneumonia (0.3%), myocardial infarction (0.3%), and deep venous thrombosis/pulmonary embolism (0.1%). Endocrine complications were the most frequent, including transient diabetes insipidus (4.3%), symptomatic hyponatremia (4.2%), new hypopituitarism (any axis) (3.6%), permanent diabetes insipidus (0.3%), and adrenal insufficiency (0.2%). There were no significant differences between microscopic and endoscopic approaches with regard to surgical complications (6.4% vs 8.8%, p = 0.247) or endocrine complications (11.4 vs 11.8%, p = 0.888). Risk factors for surgical complications included prior transsphenoidal surgery (11.4% vs 6.8%, p = 0.025), preoperative vision loss (10.3% vs 6.8%, p = 0.002), and presence of PA invasion on MRI (8.5% vs 4.4%, p = 0.007).CONCLUSIONSIn this single tertiary center study assessing complications associated with transsphenoidal PA resection, the rate of death or major disability was 0.26%. Risk factors for complications included prior surgical treatment and PA invasion. No differences in complication rates between endoscopic and microscopic surgery were observed. When performed at experienced pituitary centers, transsphenoidal surgery for PAs may be performed with a high degree of safety.

Outcomes following transsphenoidal surgical management of incidental pituitary adenomas: a series of 52 patients over a 17-year period.

OBJECTIVEIncidental pituitary adenomas (IPAs) are commonly discovered during cranial imaging evaluations obtained for unrelated indications. The optimal management of IPA remains controversial. The authors investigated the outcomes and safety of the surgical treatment of IPAs at their institution.METHODSClinical outcome data for 1692 patients surgically treated for pituitary adenomas at the Keck Medical Center of USC/USC Pituitary Center over a 17-year period (1999-2016) were reviewed to identify all cases with surgically managed IPAs. Clinical characteristics reviewed in this retrospective analysis included patient demographics, endocrine laboratory data, visual field examinations, and MRI results. Intraoperative data reviewed included requirement for CSF leak repair, surgical complications, and estimated extent of resection. Postoperative data collected included pathology results, length of stay, postoperative complications, endocrine outcomes, readmission rates, and long-term outcomes, including extent of resection noted on postoperative imaging studies and tumor progression and/or recurrence.RESULTSFifty-two patients (3.1% of all cases) underwent transsphenoidal surgery for IPA. The median age at surgery was 61 years (range 31-86 years). The most common reasons for neuroimaging included trauma (19%), stroke/transient ischemic attack (15%), and sinonasal disease (15%). Visual field deficits were present in 15% of bedside examinations, and among the 22 patients sent for formal testing, 54.5% were noted to have deficits. Preoperative endocrine function was normal in 69% of patients, which includes 3 patients (5.8%) having isolated hyperprolactinemia consistent with a stalk effect without other hormonal dysfunction. The average maximal tumor diameter was 20.9 mm (8-50 mm; data available in 35 patients). The most common primary indication for surgery was compression of the chiasm or vision loss (52%); other major considerations included tumor growth, a young patient age, and identified endocrine abnormalities. Intraoperative CSF leak repair was performed in 56% of patients, and 1 patient (2%) developed postoperative CSF rhinorrhea treated with lumbar drainage. The median hospital stay was 2 days. There were no deaths or major complications. Three patients (5.8%) developed transient diabetes insipidus. Over a mean follow-up of 61 months, 4 patients (50.0%) reported improved headaches and 6 (54.5%) reported improvement in their visual deficits. Four patients (25%) had improved endocrine function, including one with resumption of menstruation and another with remission of acromegaly. One patient (2.4%) reported new postoperative headache, and none experienced worsened vision. Four patients (10.5%) developed new single-axis hypopituitarism and 1 (2.6%) developed new panhypopituitarism. The overall recurrence/progression rate on neuroimaging was 9.6% at a mean of 80 months.CONCLUSIONSTranssphenoidal resection of IPAs, when appropriate, can be performed safely at experienced treatment centers. Incidental pituitary adenomas should be evaluated and treated as indicated, especially in younger patients at risk for endocrine or visual dysfunction.

Long-term surgical outcomes following transsphenoidal surgery in patients with Rathke's cleft cysts.

OBJECTIVE: Rathke's cleft cysts (RCCs) are benign epithelial lesions of the sellar region typically treated via a transsphenoidal approach with cyst fenestration and drainage. At present, there is limited evidence to guide patient selection for operative treatment. Furthermore, there is minimal literature describing factors contributing to cyst recurrence. METHODS: The authors conducted a retrospective analysis of 109 consecutive cases of pathology-confirmed RCCs treated via a transsphenoidal approach at a single center from 1995 to 2016. The majority of cases (86.2%) involved cyst fenestration, drainage, and partial wall resection. Long-term outcomes were analyzed. RESULTS: A total of 109 surgeries in 100 patients were included, with a mean follow-up duration of 67 months (range 3-220 months). The mean patient age was 44.6 years (range 12-82 years), and 73% were women. The mean maximal cyst diameter was 14.7 mm. Eighty-eight cases (80.7%) were primary operations, and 21 (19.3%) were reoperations. Intraoperative CSF leak repair was performed in 53% of cases and was more common in reoperation cases (71% vs 48%, p < 0.001). There were no new neurological deficits or perioperative deaths. Two patients (1.8%) developed postoperative CSF leaks. Transient diabetes insipidus (DI) developed in 24 cases (22%) and permanent DI developed in 6 (5.5%). Seven cases (6.4%) developed delayed postoperative hyponatremia. Of the 66 patients with preoperative headache, 27 (44.3%) of 61 reported postoperative improvement and 31 (50.8%) reported no change. Of 31 patients with preoperative vision loss, 13 (48.1%) reported subjective improvement and 12 (44.4%) reported unchanged vision. Initial postoperative MRI showed a residual cyst in 25% of cases and no evidence of RCC in 75% of cases. Imaging revealed evidence of RCC recurrence or progression in 29 cases (26.6%), with an average latency of 28.8 months. Of these, only 10 (9.2% of the total 109 cases) were symptomatic and underwent reoperation. CONCLUSIONS: Transsphenoidal fenestration and drainage of RCCs is a safe and effective intervention for symptomatic lesions, with many patients experiencing improvement of headaches and vision. RCCs show an appreciable (although usually asymptomatic) recurrence rate, thereby mandating serial follow-up. Despite this, full RCC excision is typically not recommended due to risk of hypopituitarism, DI, and CSF leaks.