Use of Salvage Surgery or Stereotactic Radiosurgery for Multiply Recurrent Skull Base Chordomas: A Single-Institution Experience and Review of the Literature.

Introduction Chordomas are locally destructive neoplasms characterized by appreciable recurrence rates after initial multimodality treatment. We examined the outcome of salvage treatment in recurrent/progressive skull base chordomas. Methods This is a retrospective review of recurrent/progressive skull base chordomas at a tertiary urban academic medical center. The outcomes evaluated were overall survival, progression-free survival (PFS), and incidence of new toxicity. Results Eighteen consecutive patients who underwent ≥1 course of treatment (35.3% salvage surgery, 23.5% salvage radiation, and 41.2% both) were included. The median follow-up was 98.6 months (range 16-215 months). After initial treatment, the median PFS was 17.7 months (95% confidence interval [CI]: 4.9-22.6 months). Following initial therapy, age ≥ 40 had improved PFS on univariate analysis ( p = 0.03). All patients had local recurrence, with 15 undergoing salvage surgical resections and 16 undergoing salvage radiation treatments (mostly stereotactic radiosurgery [SRS]). The median PFS was 59.2 months (95% CI: 4.0-99.3 months) after salvage surgery, 58.4 months (95% CI: 25.9-195 months) after salvage radiation, and 58.4 months (95% CI: 25.9.0-98.4 months) combined. Overall survival for the total cohort was 98.7% ± 1.7% at 2 years and 92.8% ± 5.5% at 5 years. Salvage treatments were well-tolerated with two patients (11%) reporting tinnitus and one patient each (6%) reporting headaches, visual field deficits, hearing loss, anosmia, dysphagia, or memory loss. Conclusion Refractory skull base chordomas present a challenging treatment dilemma. Repeat surgical resection or SRS seems to provide adequate salvage therapy that is well-tolerated when treated at a tertiary center offering multimodality care.

Neural network modeling for prediction of recurrence, progression, and hormonal non-remission in patients following resection of functional pituitary adenomas.

PURPOSE: Functional pituitary adenomas (FPAs) cause severe neuro-endocrinopathies including Cushing's disease (CD) and acromegaly. While many are effectively cured following FPA resection, some encounter disease recurrence/progression or hormonal non-remission requiring adjuvant treatment. Identification of risk factors for suboptimal postoperative outcomes may guide initiation of adjuvant multimodal therapies. METHODS: Patients undergoing endonasal transsphenoidal resection for CD, acromegaly, and mammosomatotroph adenomas between 1992 and 2019 were identified. Good outcomes were defined as hormonal remission without imaging/biochemical evidence of disease recurrence/progression, while suboptimal outcomes were defined as hormonal non-remission or MRI evidence of recurrence/progression despite adjuvant treatment. Multivariate regression modeling and multilayered neural networks (NN) were implemented. The training sets randomly sampled 60% of all FPA patients, and validation/testing sets were 20% samples each. RESULTS: 348 patients with mean age of 41.7 years were identified. Eighty-one patients (23.3%) reported suboptimal outcomes. Variables predictive of suboptimal outcomes included: Requirement for additional surgery in patients who previously had surgery and continue to have functionally active tumor (p = 0.0069; OR = 1.51, 95%CI 1.12-2.04), Preoperative visual deficit not improved after surgery (p = 0.0033; OR = 1.12, 95%CI 1.04-1.20), Transient diabetes insipidus (p = 0.013; OR = 1.27, 95%CI 1.05-1.52), Higher MIB-1/Ki-67 labeling index (p = 0.038; OR = 1.08, 95%CI 1.01-1.15), and preoperative low cortisol axis (p = 0.040; OR = 2.72, 95%CI 1.06-7.01). The NN had overall accuracy of 87.1%, sensitivity of 89.5%, specificity of 76.9%, positive predictive value of 94.4%, and negative predictive value of 62.5%. NNs for all FPAs were more robust than for CD or acromegaly/mammosomatotroph alone. CONCLUSION: We demonstrate capability of predicting suboptimal postoperative outcomes with high accuracy. NNs may aid in stratifying patients for risk of suboptimal outcomes, thereby guiding implementation of adjuvant treatment in high-risk patients.

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.

Surgical management of clinically silent thyrotropin pituitary adenomas: A single center series of 20 patients.

Silent thyrotropin pituitary adenomas (TSHomas) are defined by absence of hyperthyroidism despite TSH immunopositivity. Data pertaining to clinical and surgical characteristics of silent TSHomas remains limited. We aim to describe the clinical presentation, pathological characteristics, and outcomes in silent TSHoma patients treated at a tertiary pituitary center. We retrospectively identified patients with histologically-proven silent TSHoma who underwent transsphenoidal resection at our center between 2000 and 2016 (n = 1244 total patients). Patients with preoperative hyperthyroidism or thyroidectomy were excluded. Twenty patients with silent TSHomas were included (1.6% of surgically treated PAs), of which 35% were reoperations. Presenting symptoms included vision loss (45%) and headache (40%). Preoperative pituitary dysfunction included hypothyroidism (40%), hypogonadotropic hypogonadism (30%), and panhypopituitarism (15%). Nineteen patients (95%) had macroadenomas (mean diameter 29.9 mm). Extrasellar growth was identified in 17 patients (85%) and 65% had cavernous sinus invasion. Immunostaining for alpha-subunit was positive in 19 patients (95%), and 75% of tumors expressed immunopositivity for hormones other than TSH. Gross total tumor resection was achieved in 9 patients (45%) on follow-up MRI. Major postoperative complications included hydrocephalus (1 patient) and cerebrospinal fluid leak with meningitis (1 patient). Tumor progression and recurrence occurred in 1 patient each (10% total) over the follow-up period (median 18.5 months). Silent TSHomas tend to be large, invasive tumors. In addition to TSH, a majority express immunopositivity for alpha-subunit and gonadotropins, thereby potentially supporting a primitive adenoma lineage and subtype. Despite reoperation in several patients, good overall outcomes with low complication rates were achieved.

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.

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.

A pilot study of fat allograft transplantation in immunocompetent rabbits for potential neurosurgical applications.

OBJECT: The authors investigated the feasibility of using fat allografts (chemically treated to reduce the host immune response) for neurosurgical applications. METHODS: Subcutaneous fat specimens collected from New Zealand White rabbits were treated with DNAse I and sodium deoxycholate to reduce immunogenicity before subcutaneous, midscapular implantation in immunocompetent recipient rabbits. Allograft incorporation and the host-allograft response were examined at 1, 6, and 11 weeks by histopathological analysis. Control specimens of autograft and untreated fat allograft implants were examined for comparison. RESULTS: The host immune response was markedly reduced in the region around the chemically treated fat allografts when compared with untreated allografts, and was similar to the tolerant host response to autografts. CONCLUSIONS: Based on their results, the authors suggest that fat allografts processed for reduced immunogenicity may be a convenient, viable alternative for neurosurgical applications.

The role of stereotactic radiosurgery in the multimodal management of growth hormone-secreting pituitary adenomas.

Growth hormone (GH)-secreting pituitary adenomas represent a common source of GH excess in patients with acromegaly. Whereas surgical extirpation of the culprit lesion is considered first-line treatment, as many as 19% of patients develop recurrent symptoms due to regrowth of previously resected adenomatous tissue or to continued growth of the surgically inaccessible tumor. Although medical therapies that suppress GH production can be effective in the management of primary and recurrent acromegaly, these therapies are not curative, and lifelong treatment is required for hormonal control. Stereotactic radiosurgery has emerged as an effective adjunctive treatment modality, and is an appealing alternative to conventional fractionated radiation therapy. The authors reviewed the growing body of literature concerning the role of radiosurgical procedures in the treatment armamentarium of acromegaly, and identified more than 1350 patients across 45 case series. In this review, the authors report that radiosurgery offers true hormonal normalization in 17% to 82% of patients and tumor growth control in 37% to 100% of cases across all series, while minimizing adverse complications. As a result, stereotactic radiosurgery represents a safe and effective treatment option in the multimodal management of primary or recurrent acromegaly secondary to GH-secreting pituitary adenomas.

Significance of postoperative fluid diuresis in patients undergoing transsphenoidal surgery for growth hormone-secreting pituitary adenomas.

OBJECT: Following successful transsphenoidal surgery in patients with growth hormone (GH)-secreting pituitary adenomas, a characteristic fluid diuresis has been described. In this paper the authors aimed to further analyze the degree of fluid diuresis as it relates to postoperative GH levels. METHODS: Between 2000 and 2008, 85 patients underwent transsphenoidal surgery for a GH-secreting adenoma at the USC University Hospital. A retrospective chart review was conducted. Postoperative fluid intake, output, and balance within 48 hours following surgery, as well as endocrinological data were recorded and analyzed. Patients with postoperative diabetes insipidus and those with insufficient data were excluded from analysis. RESULTS: Seventy-one patients were included in the analysis. The mean age was 46 years (range 16-74 years). There were 36 males (51%) and 35 females (49%). Patients with negative fluid balances at 48 hours after surgery were more than twice as likely to have a GH level of < 1.5 ng/ml (55 vs 25%, p = 0.023). At 48 hours after surgery, patients with a negative overall fluid balance had a significantly lower median GH level than those with a positive overall fluid balance (1.3 vs 2.4 ng/ml, p = 0.039). This difference was even more pronounced in patients with microadenomas and a negative overall fluid balance. By 48 hours following surgery, patients with postoperative Day 1 GH levels < 1.5 ng/ml had, on average, experienced diuresis of fluid > 1.1 L (median 1.5 L) more than patients with GH levels > 1.5 ng/ml. CONCLUSIONS: Successful resection of GH-secreting adenomas is associated with a more pronounced fluid diuresis and negative overall fluid balance within 48 hours following transsphenoidal surgery. Patients with a negative fluid balance by postoperative Day 2 have a higher likelihood of having significantly reduced postoperative GH levels that may correlate with long-term surgical remission.

Hypericin-mediated photodynamic therapy of pituitary tumors: preclinical study in a GH4C1 rat tumor model.

OBJECTIVE: Hypericin-mediated photodynamic therapy (PDT) is receiving greater interest as a potential treatment for a variety of tumors and nonmalignant disorders. PDT involves systemic administration of a photosensitizer that selectively accumulates within tumor tissue followed by focal light activation. In the presence of molecular oxygen, a photochemical reaction generates a reactive oxygen species that induces apoptosis in target cells. The purpose of this preclinical study was to evaluate the efficacy of hypericin-mediated PDT for treatment of pituitary adenoma in a rodent model. METHODS: Wistar-Furth rats were implanted with a pituitary adenoma rat cell line, GH4C1. Tumor masses were allowed to develop over 28 days; rats with tumors of comparable sizes were then assigned to three treatment groups: control (neither hypericin nor light); light only; and hypericin and light. Hypericin was administered in four doses (1 mg/kg) at 28-h intervals prior to light exposure, wherein those rats treated with light were exposed to a light source four hours after the last hypericin dose. Tumor size was measured up to 12 days after treatment. RESULTS: Over the short interval examined, hypericin-mediated PDT was not effective against large tumors greater than 1 cm(3), but this treatment significantly slowed tumor growth for tumors less than 1 cm(3). Histological evaluation and TUNEL assay of the treated tumor identified apoptotic clusters on the periphery of the PDT-treated specimens. CONCLUSIONS: Hypericin-mediated PDT shows promise in its effectiveness in the treatment of residual small tumor rests.

Nelson syndrome: historical perspectives and current concepts.

The appearance of an adrenocorticotropic hormone (ACTH)-producing tumor after bilateral adrenalectomy for Cushing disease was first described by Nelson in 1958. The syndrome that now bears his name was characterized by hyperpigmentation, a sellar mass, and increased plasma ACTH levels. The treatment of Cushing disease has changed drastically since the 1950s, when the choice was adrenalectomy. Thus, the occurrence, diagnosis, and treatment of Nelson syndrome have changed as well. In the modern era of high-resolution neuroimaging, transsphenoidal microneurosurgery, and stereotactic radiosurgery, Nelson syndrome has become a rare entity. The authors describe the history of the diagnosis and treatment of Nelson syndrome. In light of the changes described, the authors believe this disease must be reevaluated in the contemporary era and a modern paradigm adopted.

Postoperative Gamma Knife surgery for benign meningiomas of the cranial base.

OBJECT: The standard treatment for meningiomas is complete resection, but the proximity of skull base meningiomas to important neurovascular structures makes complete excision of the lesion difficult or impossible. The authors analyzed the mid- and long-term results obtained in patients treated with postresection Gamma Knife surgery (GKS) for residual or recurrent benign meningiomas of the cranial base. METHODS: Thirty-six patients with residual or recurrent benign meningiomas of the skull base following one or more surgical procedures underwent GKS. There were 31 women and five men, ranging in age from 22 to 73 years. The median tumor volume was 4.1 ml (range 0.8-20 ml) and the median radiation dose to the tumor margin was 16 Gy (range 15-16 Gy). RESULTS: Patients were followed for a median of 81 months (range 30-141 months) after GKS. At the end of the follow-up period, overall neurological improvement was observed in 16 patients (44.4%), whereas the condition in 20 patients (55.6%) was unchanged. One patient suffered transient cerebral edema 6 months after GKS. Based on imaging documentation, a partial response was seen in five patients (13.9%), the disease remained stable in 30 patients (83.3%), and in one patient (2.8%) there was an increase in tumor size. The actuarial progression-free survival rate was 100% at 5 years and 94.7% at 10 years. CONCLUSIONS: Gamma Knife surgery was shown to be an excellent adjunct to resection because of its durable rate of tumor control and low toxicity. It should be initially considered along with surgery for the treatment of complex skull base meningiomas.