Pituitary Adenomas Associated with Intracranial Aneurysms: the Clinical Characteristics, Therapeutic Strategies, and Possible Effects of Vascular Remodeling Factors

Background Pituitary adenoma coexists with intracranial aneurysms in 2.3 to 3.6% of cases, and intracranial aneurysms are thought to be incidental. On the other hand, older age and cavernous sinus invasion are reported to increase the rate of coexistence, so these two diseases may be related. Methods Ten males and 14 females with the coexistence of pituitary adenomas and intracranial aneurysms were retrospectively investigated among 923 patients (2.6%). Patients were subdivided into two groups: those with direct attachment of cerebral aneurysms to the pituitary adenomas and those without direct attachment. The clinical characteristics, therapeutic strategies, and possible effects of vascular remodeling factors were investigated. Results Twelve patients had functioning pituitary adenomas, and cavernous sinus invasion was identified in 7 of 24 patients. Five of these 7 patients were treated with priority for the cerebral aneurysm until 2007, whereas 14 of 17 patients without involvement of the aneurysm tip in the tumor were treated with priority for the pituitary adenoma in the later period. Among vascular remodeling factors, strong expression of vascular endothelial growth factor (VEGF) was significantly associated with the coexistence of pituitary adenoma and cerebral aneurysm (p < 0.05). Conclusion Intracranial aneurysms were found to coexist in 2.6% of cases of surgically treated pituitary adenomas. VEGF-induced arterial wall remodeling may be part of the mechanism of association between pituitary adenomas and cerebral aneurysms, suggesting possible causative mechanism.

Pituitary MRI standard and advanced sequences: role in the diagnosis and characterization of pituitary adenomas

Pituitary adenomas (PAs) represent the most frequently found lesions in the sellar region; however, several other lesions may be encountered in this region, such as meningiomas, craniopharyngiomas and aneurysms. High-quality imaging is fundamental for diagnosis, characterization and guidance of treatment planning of PAs. Sellar magnetic resonance imaging (MRI) is considered the imaging modality of choice for the evaluation of lesions in the sella turcica. The sellar MRI standard protocol includes coronal and sagittal T1-weighted (T1w) spin-echo sequencing with and without gadolinium-based contrast agent and coronal T2-weighted (T2w) fast-spin echo sequencing. A systematic MRI approach to the pituitary region generally provides information that includes the size and shape of the PA, the presence of cysts or hemorrhage within the tumor, its relationship with the optic pathways and surrounding structures, potential cavernous sinus invasion, sphenoid sinus pneumatization type, and differential diagnosis with other sellar lesions. The standard protocol is sufficient for the evaluation of most cases; however, some advanced techniques (susceptibility imaging, diffusion-weighted imaging, 3D T2w high-resolution sequences, magnetic resonance elastography, perfusion-weighted imaging) may render additional information, which may be important for some cases. In this “Approach to the Patient” manuscript we will discuss the use of standard and advanced MRI sequences in the diagnosis and characterization of PAs, including MRI features associated with treatment response that may aid in presurgical evaluation and planning, and red flags that may point to an alternative diagnosis.

Quantification of Tumor Blush of Highly Vascularized Tumors with Slow Feeding System: Representative Use for Giant Pituitary Adenomas

abstract Background Modern imaging techniques can identify adverse factors for tumor removal such as cavernous sinus invasion before surgery, but surgeries for giant pituitary adenomas often reveal discrepancies between preoperative imaging and intraoperative findings because pituitary adenomas have feeding arteries with narrow diameters. Current imaging methods are not suitable for tumors with not only large vascular beds but also slow arterial filling. Patients and Methods This prospective study recruited 13 male subjects and 9 female subjects with giant pituitary adenomas between November 2011 and 2018. All the patients were investigated with three-dimensional magnetic resonance (MR) imaging, bone image computerized tomography (CT), and digital subtraction angiography (DSA) using a C-arm cone-beam CT scanner with a flat-panel detector and 50% diluted contrast medium. Fine angioarchitecture was evaluated and the tumor blush was quantified using newly developed region of interest (ROI) analysis to establish surgical strategies. Results Seven patients demonstrated no or very faint tumor blushes. In these patients, feeding arteries run centripetally from the surface of the tumor. Fifteen patients showed significant tumor blushes, and the feeding arteries penetrated centrifugally from the inferoposterior pole to the upper pole of the tumor. All the patients were treated according to the angiographic information with successful hemostasis. The patients showed improvement and/or disappearance of the neurologic deficits. The faint and significant blush groups showed significant differences in intraoperative bleeding (p < 0.01) and operation time (p < 0.05). Conclusion Specialized evaluation focused on vascularization is required for successful therapy of giant pituitary adenomas.

Racial disparities in acromegaly and Cushing’s disease: a referral center study in 241 patients

Purpose The impact of race on presentation and postoperative outcomes in adults with acromegaly (ACM) and Cushing’s disease (CD) has not been evaluated. Methods This is a retrospective study of consecutive patients operated at a large-volume pituitary center. We evaluated: 1) racial distribution of patients residing in the metropolitan area (Metro, N=124) versus 2010 U.S. Census data, 2) presentation and postoperative outcomes in Black versus White for patients from the entire catchment area (N=241). Results For Metro area (32.4% Black population), Black patients represented 16.75% ACM (p=0.006) and 29.2% CD (p=0.56).Among 112 total ACM patients, presentations with headaches or incidentaloma were more common in Black patients (76.9% versus 31% White, p=0.01). Black patients had a higher prevalence of diabetes (54% versus 16% White, p=0.005), significantly lower IGF-1 deviation from normal (p=0.03) and borderline lower median GH levels (p=0.09). Mean tumor diameter and proportion of tumors with cavernous sinus invasion were similar. Three-month biochemical remission (46% Black, 55% White, p=0.76) and long-term IGF-1 control by multimodality therapy (92.3% Black, 80.5% White, p=0.45) were similar. Among 129 total CD patients, Black patients had more hypopituitarism (69% vs 45% White, p=0.04) and macroadenomas (33% vs 15% White, p=0.05). At 3 months, remission rate was borderline higher in White (92% vs 78% Black, p=0.08) which was attributed to macroadenomas by logistic regression. Conclusion We identified disparities regarding racial distribution, clinical and biochemical characteristics in ACM, suggesting late or missed diagnosis in Black patients. Large nationwide studies are necessary to confirm our findings.

Postoperative GH and Degree of Reduction in IGF-1 Predicts Postoperative Hormonal Remission in Acromegaly

PurposeDetermine predictive factors for long-term remission of acromegaly after transsphenoidal resection of growth hormone (GH)-secreting pituitary adenomas.MethodsWe identified 94 patients who had undergone transsphenoidal resection of GH-secreting pituitary adenomas for treatment of acromegaly at the USC Pituitary Center from 1999-2019 to determine the predictive value of postoperative endocrine lab values.ResultsPatients underwent direct endoscopic endonasal (60%), microscopic transsphenoidal (38%), and extended endoscopic approaches (2%). The cohort was 63% female and 37% male, with average age of 48.9 years. Patients presented with acral enlargement (72, 77%), macroglossia (40, 43%), excessive sweating (39, 42%), prognathism (38, 40%) and frontal bossing (35, 37%). Seventy-five (80%) were macroadenomas and 19 (20%) were microadenomas. Cavernous sinus invasion was present in 45%. Available immunohistochemical data demonstrated GH staining in 88 (94%) and prolactin in 44 (47%). Available postoperative MRI demonstrated gross total resection in 63% of patients and subtotal resection in 37%. Most patients (66%) exhibited hormonal remission at 12 weeks postoperatively. Receiver operating characteristic (ROC) curves demonstrated postoperative day 1 (POD1) GH levels ≥1.55ng/mL predicted failure to remit from surgical resection alone (59% specificity, 75% sensitivity). A second ROC curve showed decrease in corrected insulin-like growth factor-1 (IGF-1) levels of at least 37% prognosticated biochemical control (90% sensitivity, 80% specificity).ConclusionPOD1 GH and short-term postoperative IGF-1 levels can be used to successfully predict immediate and long-term hormonal remission respectively. A POD1 GH cutoff can identify patients likely to require adjuvant therapy to emphasize clinical follow-up.

Predicting pituitary adenoma consistency with preoperative magnetic resonance elastography

OBJECTIVE Pituitary adenoma is one of the most common primary intracranial neoplasms. Most of these tumors are soft, but up to 17% may have a firmer consistency. Therefore, knowing the tumor consistency in the preoperative setting could be helpful. Multiple imaging methods have been proposed to predict tumor consistency, but the results are controversial. This study aimed to evaluate the efficacy of MR elastography (MRE) in predicting tumor consistency and its potential use in a series of patients with pituitary adenomas. METHODS Thirty-eight patients with pituitary adenomas (≥ 2.5 cm) were prospectively evaluated with MRI and MRE before surgery. Absolute MRE stiffness values and relative MRE stiffness ratios, as well as the relative ratio of T1 signal, T2 signal, and diffusion-weighted imaging apparent diffusion coefficient (ADC) values were determined prospectively by calculating the ratio of those values in the tumor to adjacent left temporal white matter. Tumors were classified into three groups according to surgical consistency (soft, intermediate, and firm). Statistical analysis was used to identify the predictive value of the different radiological parameters in determining pituitary adenoma consistency. RESULTS The authors included 32 (84.21%) nonfunctional and 6 (15.79%) functional adenomas. The mean maximum tumor diameter was 3.7 cm, and the mean preoperative tumor volume was 16.4 cm3. Cavernous sinus invasion was present in 20 patients (52.63%). A gross-total resection was possible in 9 (23.68%) patients. The entire cohort’s mean absolute tumor stiffness value was 1.8 kPa (range 1.1–3.7 kPa), whereas the mean tumor stiffness ratio was 0.66 (range 0.37–1.6). Intraoperative tumor consistency was significantly correlated with absolute and relative tumor stiffness (p = 0.0087 and 0.007, respectively). Tumor consistency alone was not a significant factor for predicting gross-total resection. Patients with intermediate and firm tumors had more complications compared to patients with soft tumors (50.00% vs 12.50%, p = 0.02) and also had longer operative times (p = 0.0002). CONCLUSIONS Whereas other MRI sequences have proven to be unreliable in determining tumor consistency, MRE has been shown to be a reliable tool for predicting adenoma consistency. Preoperative knowledge of tumor consistency could be potentially useful for surgical planning, counseling about potential surgical risks, and estimating the length of operative time.

gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.

Primary intracranial aggressive fibromatosis arising in sella turcica: illustrative case

BACKGROUND Aggressive fibromatosis is a rare histologically benign but locally infiltrative myofibroblastic tumor. Primary intracranial aggressive fibromatosis (IAF) can exhibit a clinically malignant course. OBSERVATIONS A 22-year-old otherwise healthy woman presented with left painful ophthalmoplegia. Magnetic resonance imaging (MRI) revealed a left sellar tumor with cavernous sinus invasion. Endoscopic transsphenoidal surgery was performed. The lesion could not be totally resected. An inflammatory myofibroblastic tumor was suspected, so steroid pulse therapy was introduced, but it was ineffective. The tumor recurred after a few months, and she complained of visual acuity loss, abducens nerve palsy, trigeminal neuralgia, and panhypopituitarism. The lesion was diagnosed as primary IAF by a pathological review. Gamma Knife radiosurgery was performed, and chemotherapies were introduced but ineffective. Her consciousness was disturbed, and MRI showed hypothalamic invasion of the tumor, occlusion and stenosis of carotid arteries, and cerebral stroke. Palliative care was introduced, and she died 32 months after the onset. The autopsy revealed tumor invasion to the cavernous sinus, optic nerve, hypothalamus, pituitary, and tonsillar herniation due to massive cerebral stroke. LESSONS Radical resection can be impossible in patients with IAF. Radiotherapy and chemotherapy are not always effective for residual lesions. Adjuvant therapy for IAF remains to be explored.

Association of different pathologic subtypes of growth hormone producing pituitary adenoma and remission in acromegaly patients: a retrospective cohort study

Background Regarding the inconclusive results of previous investigations, this study aimed to determine the association between pathology, as a possible predictor, with remission outcomes, to know the role of pathology in the personalized decision making in acromegaly patients. Methods A retrospective cohort study was performed on the consecutive surgeries for growth hormone (GH) producing pituitary adenomas from February 2015 to January 2021. Seventy-one patients were assessed for granulation patterns and prolactin co-expression as dual staining adenomas. The role of pathology and some other predictors on surgical remission was evaluated using logistic regression models. Results Among 71 included patients, 34 (47.9%) patients had densely granulated (DG), 14 (19.7%) had sparsely granulated (SG), 23 (32.4%) had dual staining pituitary adenomas. The remission rate was about 62.5% in the patients with SG and DG adenomas named single staining and 52.2% in dual staining groups. Postoperative remission was 1.53-folds higher in the single staining adenomas than dual staining-one (non-significant). The remission rate was doubled in DG group compared to two other groups (non-significant). By adjusting different predictors, cavernous sinus invasion and one-day postoperative GH levels decreased remission rate by 91% (95% CI: 0.01–0.67; p = 0.015) and 64% (95% CI: 0.19–0.69; p < 0.001), respectively. Responses to the medications were not significantly different among three groups. Conclusion Various pathological subtypes of pituitary adenomas do not appear to have a predictive role in estimating remission outcomes. Cavernous sinus invasion followed by one-day postoperative GH is the strongest parameter to predict biochemical remission.