Adamantinomatous craniopharyngioma associated with a compromised blood-brain barrier: patient series.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is a highly morbid adult and pediatric brain tumor derived from epithelial remnants of the craniopharyngeal canal (Rathke's pouch), which gives rise to the anterior pituitary gland. Standard therapy includes maximal safe resection with or without radiation therapy. Systemic antitumor therapy remains elusive. Immune-related paracrine signaling involving the interleukin-6 receptor (IL-6R) may contribute to ACP pathogenesis. Tocilizumab, a recombinant humanized monoclonal antibody against IL-6R, is approved by the US Food and Drug Administration but does not cross an intact blood-brain barrier. OBSERVATIONS: In a phase 0 trial design, a single dose of tocilizumab was delivered intravenously before clinically indicated surgical intervention in 3 children with ACP. The presence of tocilizumab was assayed in plasma, tumor tissue, tumor cyst fluid, and cerebrospinal fluid (n = 1) using a novel enzyme-linked immunosorbent assay. Tocilizumab reached ACP tumor tissue and/or cyst fluid after one systemic dose in every patient. LESSONS: This finding helps explain extant data that indicate tocilizumab may contribute to ACP therapy. It further indicates that ACP does not reside behind an intact blood-brain barrier, dramatically broadening the range of potential antitumor therapies against this tumor. This has substantial implications for the design of future clinical trials for novel therapies against ACP in both children and adults.

Papillary craniopharyngioma in a patient following resection of nonfunctioning pituitary adenoma: illustrative case.

BACKGROUND: Although craniopharyngioma and pituitary adenoma are common tumors of the sellar or suprasellar region, the development of papillary craniopharyngioma in the same sellar region after resection of a nonfunctioning pituitary adenoma has not been reported. OBSERVATIONS: Here the authors report the first case of craniopharyngioma that developed long after resection of a pituitary adenoma. A 66-year-old male patient underwent endoscopic transsphenoidal resection for a large sellar mass, which histopathologically confirmed the diagnosis of a pituitary adenoma. He had an excellent recovery after surgery. For several years, he had no clinical or imaging evidence of tumor recurrence and then was lost to follow-up. Seven years after the initial surgery, the patient returned with a one-month history of visual field defects, and imaging confirmed a heterogeneous, cystic suprasellar mass. Endoscopic transsphenoidal resection of the tumor was performed, and histological examination showed it to be a papillary craniopharyngioma. LESSONS: Neurosurgeons should be aware that after pituitary adenoma resection, a recurrent mass could be a craniopharyngioma, with implications for very different management recommendations.

Adamantinomatous craniopharyngioma: moving toward targeted therapies.

The evolving characterization of the biological basis of adamantinomatous craniopharyngioma (ACP) has provided insights critical for novel systemically delivered therapies. While current treatment strategies for ACP are associated with low mortality rates, patients experience severely lowered quality of life due to high recurrence rates and chronic sequelae, presenting a need for novel effective treatment regimens. The identification of various dysregulated pathways that play roles in the pathogenesis of ACP has prompted the investigation of novel treatment options. Aberrations in the CTNNB1 gene lead to the dysregulation of the Wnt pathway and the accumulation of nuclear ß-catenin, which may play a role in tumor invasiveness. While Wnt pathway/ß-catenin inhibition may be a promising treatment for ACP, potential off-target effects have limited its use in current intervention strategies. Promising evidence of the therapeutic potential of cystic proinflammatory mediators and immunosuppressants has been translated into clinical therapies, including interleukin 6 and IDO-1 inhibition. The dysregulation of the pathways of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 and its ligand (PD-1/PD-L1) has led to identification of various therapeutic targets that have shown promise as clinical strategies. The Sonic Hedgehog (SHH) pathway is upregulated in ACP and has been implicated in tumorigenesis and tumor growth; however, inhibition of SHH in murine models decreased survival, limiting its therapeutic application. While further preclinical and clinical data are needed, systemically delivered therapies could delay or replace the need for more aggressive definitive treatments. Ongoing preclinical investigations and clinical trials of these prospective pathways promise to advance treatment approaches aimed to increase patients' quality of life.

Interrater reliability of a method to assess hypothalamic involvement in pediatric adamantinomatous craniopharyngioma.

OBJECTIVE: Pediatric adamantinomatous craniopharyngiomas (ACPs) are histologically benign brain tumors that confer significant neuroendocrine morbidity. Previous studies have demonstrated that injury to the hypothalamus is associated with worsened quality of life and a shorter lifespan. This insight helps many surgeons define the goals of surgery for patients with ACP. Puget and colleagues proposed a 3-tiered preoperative and postoperative grading system based on the degree of hypothalamic involvement identified on MRI. In a prospective cohort from their institution, the authors found that use of the system to guide operative goals was associated with decreased morbidity. To date, however, the Puget system has not been externally validated. Here, the authors present an interrater reliability study that assesses the generalizability of this system for surgeons planning initial operative intervention for children with craniopharyngiomas. METHODS: A panel of 6 experts, consisting of pediatric neurosurgeons and pediatric neuroradiologists, graded 30 preoperative and postoperative MRI scans according to the Puget system. Interrater reliability was calculated using Fleiss' κ and Krippendorff's α statistics. RESULTS: Interrater reliability in the preoperative context demonstrated moderate agreement (κ = 0.50, α = 0.51). Interrater reliability in the postoperative context was 0.27 for both methods of statistical evaluation. CONCLUSIONS: Interrater reliability for the system as defined is moderate. Slight refinements of the Puget MRI grading system, such as collapsing the 3 grades into 2, may improve its reliability, making the system more generalizable.

Identification of tumor stem-like cells in admanatimomatous craniopharyngioma and determination of these cells' pathological significance.

OBJECTIVE: Nuclear ß-catenin, a hallmark of active canonical Wnt signaling, can be histologically detected in a subset of cells and cell clusters in up to 94% of adamantinomatous craniopharyngioma (ACP) samples. However, it is unclear whether nuclear ß-catenin-containing cells within human ACPs possess the characteristics of tumor stem cells, and it is unknown what role these cells have in ACP. METHODS: Primary ACP cells were cultured from 12 human ACP samples. Adamantinomatous CP stem cell-like cells (CSLCs) showing CD44 positivity were isolated from the cultured primary ACP cells by performing magnetic-activated cell sorting. The tumor sphere formation, cell cycle distribution, stemness marker expression, and multidifferentiation potential of the CD44- cells and the CSLCs were analyzed. RESULTS: Compared with the CD44- cells, the cultured human CSLCs formed tumor spheres and expressed CD44 and CD133; moreover, these cells demonstrated nuclear translocation of ß-catenin. In addition, the CSLCs demonstrated osteogenic and adipogenic differentiation capacities compared with the CD44- cells. The CSLCs also displayed the capacity for tumor initiation in human-mouse xenografts. CONCLUSIONS: These results indicate that CSLCs play an important role in ACP development, calcification, and cystic degeneration.

Clinical features and operative technique of transinfundibular craniopharyngioma.

OBJECTIVE: Transinfundibular craniopharyngioma (TC) is one of the 4 subtypes of suprasellar craniopharyngioma. In this study, the authors analyzed the clinical features of and operative technique for TC. METHODS: A total of 95 consecutive cases of suprasellar craniopharyngioma that had been resected via the endoscopic expanded endonasal approach were retrospectively reviewed. Patients were divided into 2 groups: 34 in the TC group and 61 in the nontransinfundibular craniopharyngioma (NC) group. Clinical and radiographic features, intraoperative findings, histopathological and genetic findings, and surgical outcomes were analyzed and compared between groups. RESULTS: Compared with NC, TC was mostly seen in adult patients (97.1%); it was rare in children (2.9%). Clinical presentations tended toward headache, hydrocephalus, and diabetes insipidus. The relatively smaller volume, midline location (consistent with the stalk position), unidentifiable stalk, no shift of the third ventricle, and greater likelihood to involve the third ventricle and cause hydrocephalus were the characteristic features of TC in the preoperative MRI study. According to the degree of vertical extension of the tumor, the 34 TCs could be classified into 3 subtypes: type 1, entity was limited to stalk (n = 2, 5.9%); type 2, tumor extended up to the third ventricle (type 2a) or down to the subdiaphragmatic cavity (type 2b) (n = 23, 67.6%); and type 3, tumor extended in both directions (n = 9, 26.5%). For TC resection, the chiasm-pituitary corridor, lamina terminalis corridor, and pituitary corridor could be used separately or jointly. Most of the TCs originated from the infundibulum-tuber cinereum, grew within and along the long axis of the infundibulum, and the pituitary stalk was not usually preserved in TCs (20.6%), whereas the rate of preservation was higher (80.3%) in NCs. Bilateral hypothalamic injury was found in nearly all TCs if radical resection was performed, whereas the relationship between NCs and hypothalamus was either compression (32.8%) or unilateral invasion (67.2%). Meanwhile, the postoperative endocrine and neuropsychological function outcomes in patients with TC were worse than in patients with NC. The genetic analysis with whole-exome sequencing studies showed no differential mutations of CTNNB1 (ß-catenin) and BRAF (V600E) between TC and NC subtypes, but there was a difference between adamantinomatous craniopharyngioma and papillary craniopharyngioma. CONCLUSIONS: TC is a special subtype of suprasellar craniopharyngioma, which is remarkably different from NC. Identification of this type of tumor preoperatively is essential for the planning of appropriate surgical approach and degree of excision.

Craniopharyngioma: a roadmap for scientific translation.

OBJECTIVE Craniopharyngiomas are among the most challenging of intracranial tumors to manage because of their pattern of growth, associated morbidities, and high recurrence rate. Complete resection on initial encounter can be curative, but it may be impeded by the risks posed by the involved neurovascular structures. Recurrent craniopharyngiomas, in turn, are frequently refractory to additional surgery and adjuvant radiation or chemotherapy. METHODS The authors conducted a review of primary literature. RESULTS Recent advances in the understanding of craniopharyngioma biology have illuminated potential oncogenic targets for pharmacotherapy. Specifically, distinct molecular profiles define two histological subtypes of craniopharyngioma: adamantinomatous and papillary. The discovery of overactive B-Raf signaling in the adult papillary subtype has led to reports of targeted inhibitors, with a growing acceptance for refractory cases. An expanding knowledge of the biological underpinnings of craniopharyngioma will continue to drive development of targeted therapies and immunotherapies that are personalized to the molecular signature of each individual tumor. CONCLUSIONS The rapid translation of genomic findings to medical therapies for recurrent craniopharyngiomas serves as a roadmap for other challenging neurooncological diseases.

Do craniopharyngioma molecular signatures correlate with clinical characteristics?

OBJECTIVE Exome sequencing studies have recently demonstrated that papillary craniopharyngiomas (PCPs) and adamantinomatous craniopharyngiomas (ACPs) have distinct genetic origins, each primarily driven by mutually exclusive alterations: either BRAF ( V600E), observed in 95% of PCPs, or CTNNB1, observed in 75%-96% of ACPs. How the presence of these molecular signatures, or their absence, correlates with clinical, radiographic, and outcome variables is unknown. METHODS The pathology records for patients who underwent surgery for craniopharyngiomas between May 2000 and March 2015 at Weill Cornell Medical College were reviewed. Craniopharyngiomas were identified and classified as PCP or ACP. Patients were placed into 1 of 3 groups based on their genomic mutations: BRAF mutation only, CTNNB1 mutation only, and tumors with neither of these mutations detected (not detected [ND]). Demographic, radiological, and clinical variables were collected, and their correlation with each genomic group was tested. RESULTS Histology correlated strongly with mutation group. All BRAF tumors with mutations were PCPs, and all CTNNB1 with mutations and ND tumors were ACPs. Preoperative and postoperative clinical symptoms and radiographic features did not correlate with any mutation group. There was a statistically significant relationship (p = 0.0323) between the age group (pediatric vs adult) and the mutation groups. The ND group tumors were more likely to involve the sella (p = 0.0065). CONCLUSIONS The mutation signature in craniopharyngioma is highly predictive of histology. The subgroup of tumors in which these 2 mutations are not detected is more likely to occur in children, be located in the sella, and be of ACP histology.

Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice.

Since the first identification of CTNNB1 mutations in adamantinomatous craniopharyngioma (ACP), much has been learned about the molecular pathways and processes that are disrupted in ACP pathogenesis. To date this understanding has not translated into tangible patient benefit. The recent development of novel techniques and a range of preclinical models now provides an opportunity to begin to support treatment decisions and develop new therapeutics based on molecular pathology. In this review the authors summarize many of the key findings and pathways implicated in ACP pathogenesis and discuss the challenges that need to be tackled to translate these basic science findings for the benefit of patients.

Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin.

OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated. METHODS The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures. RESULTS In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA. CONCLUSIONS These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.

Diagnosis and management of craniopharyngiomas in the era of genomics and targeted therapy.

Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute-sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma. In this new era of genomic discovery, the treatment paradigm of craniopharyngioma is likely to change.

Potential evolution of neurosurgical treatment paradigms for craniopharyngioma based on genomic and transcriptomic characteristics.

The recent genomic and transcriptomic characterization of human craniopharyngiomas has provided important insights into the pathogenesis of these tumors and supports that these tumor types are distinct entities. Critically, the insights provided by these data offer the potential for the introduction of novel therapies and surgical treatment paradigms for these tumors, which are associated with high morbidity rates and morbid conditions. Mutations in the CTNNB1 gene are primary drivers of adamantinomatous craniopharyngioma (ACP) and lead to the accumulation of ß-catenin protein in a subset of the nuclei within the neoplastic epithelium of these tumors. Dysregulation of epidermal growth factor receptor (EGFR) and of sonic hedgehog (SHH) signaling in ACP suggest that paracrine oncogenic mechanisms may underlie ACP growth and implicate these signaling pathways as potential targets for therapeutic intervention using directed therapies. Recent work shows that ACP cells have primary cilia, further supporting the potential importance of SHH signaling in the pathogenesis of these tumors. While further preclinical data are needed, directed therapies could defer, or replace, the need for radiation therapy and/or allow for less aggressive surgical interventions. Furthermore, the prospect for reliable control of cystic disease without the need for surgery now exists. Studies of papillary craniopharyngioma (PCP) are more clinically advanced than those for ACP. The vast majority of PCPs harbor the BRAFv600e mutation. There are now 2 reports of patients with PCP that had dramatic therapeutic responses to targeted agents. Ongoing clinical and research studies promise to not only advance our understanding of these challenging tumors but to offer new approaches for patient management.

Growth patterns of craniopharyngiomas: clinical analysis of 226 patients.

OBJECT Craniopharyngiomas (CPs) are rare epithelial tumors that are often associated with an enigmatic and unpredictable growth pattern. Understanding the growth patterns of these tumors has a direct impact on surgical planning and may enhance the safety of radical tumor removal. The aim of this study was to analyze the growth patterns and surgical treatment of CPs with a focus on the involvement of the hypothalamopituitary axis and the relationship of the tumor to the arachnoid membrane and surrounding structures. METHODS Clinical data from 226 consecutive patients with primary CP were retrospectively reviewed. Tumor location and the relationship of the tumor to the third ventricle floor and the pituitary stalk were evaluated using preoperative MRI and intraoperative findings. A topographic classification scheme was proposed based on the site of tumor origin and tumor development. The clinical relevance of this classification on patient presentation and outcomes was also analyzed. RESULTS The growth of CPs can be broadly divided into 3 groups based on the site of tumor origin and on tumor-meningeal relationships: Group I, infrasellar/infradiaphragmatic CPs (Id-CPs), which mainly occurred in children; Group II, suprasellar subarachnoid extraventricular CPs (Sa-CPs), which were mainly observed in adults and rarely occurred in children; and Group III, suprasellar subpial ventricular CPs (Sp-CPs), which commonly occurred in both adults and children. Tumors in each group may develop complex growth patterns during vertical expansion along the pituitary stalk. Tumor growth patterns were closely related to both clinical presentation and outcomes. Patients with Sp-CPs had more prevalent weight gain than patients with Id-CPs or Sa-CPs; the rates of significant weight gain were 41.7% for children and 16.7% for adults with Sp-CPs, 2.2% and 7.1% for those with Id-CPs, and 12.5% and 2.6% for those with Sa-CPs (p < 0.001). Moreover, patients with Sp-CPs had increased hypothalamic dysfunction after radical removal; 39% of patients with Sp-CPs, 14.5% with Id-CPs, and 17.4% with Sa-CPs had high-grade hypothalamic dysfunction in the first 2 postoperative years (p < 0.001). CONCLUSIONS The classification of CPs based on growth pattern may elucidate the best course of treatment for this formidable tumor. More tailored, individualized surgical strategies based on tumor growth patterns are mandatory to provide long-term tumor control and to minimize damage to hypothalamic structures. Differences in the distribution of growth patterns between children and adults imply that hierarchical comparison is necessary when investigating outcomes and survival across treatment paradigms in patients with CP.