Papillary Craniopharyngioma Research Articles

CTNI-73. ALLIANCE A071601: PHASE II TRIAL OF BRAF/MEK INHIBITION IN NEWLY DIAGNOSED PAPILLARY CRANIOPHARYNGIOMAS

Abstract BACKGROUND Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation. METHODS Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial. RESULTS Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events. CONCLUSIONS Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.

PATH-59. SYSTEMATIC CHARACTERIZATION OF ANTIBODY-DRUG CONJUGATE TARGETS IN CENTRAL NERVOUS SYSTEM TUMORS

Abstract BACKGROUND Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid cancers, including those expressing ERBB2/HER2, TACSTD2/TROP2, NECTIN4, folate receptor 1 (FOLR1), and tissue factor (CD142/TF). Recently, a next-generation ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level ADC target expression may be sufficient for treatment responsiveness, and CNS tumors may be responsive to next-generation ADC. However, ADC target expression is poorly characterized in most CNS tumors. METHODS To systematically characterize ADC target expression in CNS tumors, we analyzed publicly available RNA-sequencing and proteomic data from the Children’s Brain Tumor Network (n=188 tumors) and GEO RNA-expression datasets (n=356 tumors) to evaluate expression of 14 potential ADC targets that are FDA-approved or under clinical investigation in solid cancers. We also used immunohistochemistry to score the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma (GBM), oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (n=575 total tumors). RESULTS Multi-modal pan-CNS analysis showed consistent subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas (n=44) strongly expressed HER2 (36/44; 81% of cases by IHC), while meningiomas weakly-moderately expressed HER2 in most tumors (201/234; 86%). ACP (n=15) and PCP (n=3) strongly expressed B7-H3 (100% of cases), with TROP2 and HER2 expression in whorled ACP epithelium (100% of cases). AT/RT strongly expressed CLDN6 (8/9; 89%). GBM showed little subtype-specific marker expression, suggesting a need for further target development. CONCLUSIONS CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be fruitful.

Systematic characterization of antibody-drug conjugate targets in central nervous system tumors.

Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors. We analyzed publicly available RNA-sequencing and proteomic data from the children's brain tumor network (N = 188 tumors) and gene-expression-omnibus RNA-expression datasets (N = 356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N = 575). Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma showed little subtype-specific marker expression, suggesting a need for further target development. CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be warranted.

A Full View of Papillary Craniopharyngioma Based on Expanded Endonasal Approach: A Comprehensive Clinical Characterization of 101 Cases.

The enlarged endonasal approach (EEA) has emerged as the preferred surgical procedure for removing craniopharyngiomas, due to its advantages of direct visualization and reduction of blind corners. However, owing to a low incidence of papillary CPs (PCPs) compared to adamantinomatous CPs (ACPs), a full view of PCP based on the EEA approach is limited. In this paper, the authors present the largest series to date analyzing the clinical characteristics based on the EEA approach for PCPs. A retrospective review was conducted on 101 PCPs patients who underwent endoscopic endonasal surgery (EEA) and whose condition was confirmed via postoperative pathology. The PCPs were classified into three types based on MRI data and intraoperative findings from EEA: suprasellar/intra-suprasellar (3V floor intact) type (Type I), suprasellar/intra-suprasellar (3V floor invasive) type (Type II), and intra-third ventricle type (Type III). The general characteristics of the three types of tumors were summarized, and postoperative follow-up was conducted to record detailed information on changes in vision, endocrine replacement, tumor recurrence, and quality of life. Out of the 101 cases, 36 (36.64%) were classified as type I, 52 (51.49%) as type II, and 13 (12.87%) as type III. The mean age of type III patients was 40.46 ± 14.15 years old, younger than the other two types (p = 0.021). Headache (84.62%) and memory decline (61.54%) were prominent features in patients with type III (p = 0.029). Visual impairment was more common in type II (80.77%, p = 0.01). Gross total resection (GTR) was achieved in 91 patients (90.10%). There were no significant differences in GTR rates among the three types of tumors. There were significant differences in quality of life among the three types of PCP (p = 0.004), and type III presented with the highest rate of good postoperative quality of life (92.31%) based on the KPS score. Thirteen (12.87%) tumors recurred within a mean follow-up time of 38 (range, 8-63) months. Type II PCPs (OR 5.826, 95%CI 1.185-28.652, p = 0.030) and relapsed patients (OR 4.485, 95%CI 1.229-16.374, p = 0.023) were confirmed as independent risk factors for tumor recurrence. Most of the PCPs including intra-third ventricle PCPs can be safely and effectively removed through neuroendoscopy with EEA. Suprasellar/intra-suprasellar (third cerebral ventricle floor-invasive) type PCPs may have a worse postoperative quality of life compared to the other two types, and it may be a strong predictor of tumor recurrence.

THU102 A Case Of Papillary Craniopharyngioma WHO Grade 1 Turned Into Abscess

Abstract Disclosure: R.J. Shah: None. J. Patel: None. P.A. Belany: None. Craniopharyngioma is a rare primary brain tumor located in the suprasellar region. Papillary craniopharyngiomas (PC) occur mostly in adults, between age 40-50. Despite surgery being the primary treatment, PCs have a high tendency for relapse. We present a case of PC WHO grade 1, positive for BRAF V600E mutation concerning for regrowth 10 months following surgical resection. A 45-year-old male presented to the emergency department with complaint of right orbital headaches, vision change and severe fatigue. CT head was normal and was discharged home. Headaches, fatigue, and vision change progressively worsened over the next week with new symptoms of erectile dysfunction, low libido, weight loss, polyuria, polydipsia and proximal muscle weakness developing. Morning labs showed FT4 0.5ng/dl, TSH 2.32uIU, cortisol 1.5ug/dl, ACTH 14 pg/mL, FSH 1.5mIU/mL, LH 0.2mIU/mL, total testosterone 6ng/dl, prolactin 17.5ng/mL, IGF-1 134 ng/mL and GH 0.2ng/dl concerning for panhypopituitarism. Chemistry panel was unremarkable. MRI pituitary confirmed sellar mass measuring 2.1x1.3x2.1cm compressing the optic chiasm. Evaluated by endocrinology, patient was started on hydrocortisone, levothyroxine and desmopressin and referred to neurosurgery. Following endoscopic endonasal approach (EEA), pathology showed PC WHO Grade 1 and molecular testing positive for BRAF V600E mutation. Two-month post-surgical MRI showed residual 8mm lesion. Active surveillance showed regrowth of sellar lesion to 1.8 cm with optic chiasm compression ten months following EEA. Repeat EEA was done with concern for relapse. Surprisingly, intraoperative purulent fluid draining from the sella was found and positive for Acinetobacter. Sellar abscess was drained and he received six weeks of intravenous antibiotics. Repeat MRI showed resolution of the entire sellar lesion, his vision normalized and continued to be on hormone replacement for panhypopituitarism. PCs are locally aggressive suprasellar lesions that can reach a large size prior to clinical symptoms developing. Around 90% of PC are positive for BRAF V600 mutation. Surgical resection and radiotherapy are the primary treatment, but newer studies have demonstrated tumor regression using BRAF targeted agents following relapse. Our case demonstrates a pituitary abscess (PA) found intraoperatively that was originally suspicious for tumor recurrence. PA is a rare and serious intrasellar infection associated with high mortality. It is difficult to diagnose preoperatively and can be misdiagnosed as recurrence or residual tissue. PA can be primary or secondary depending on etiology. PA associated with residual craniopharyngioma tissue is extremely rare and the exact pathophysiology is not well understood. If no evidence of sepsis or meningitis, treatment with transsphenoidal decompression and intravenous antibiotics has good clinical outcomes. Presentation: Thursday, June 15, 2023

THU085 Can Genetic Mutations And Molecular Markers Predict Recurrence In Adamantinomatous Or Papillary Craniopharyngiomas? A Systemic Review.

Abstract Disclosure: M. Nicholas: None. U. Mahfuza: None. A. De Ieva: None. M. Rodriguez: None. V.A. Preda: None. Craniopharyngiomas are rare, but clinically significant intracranial tumors. According to the WHO criteria, two clinicopathological subtypes, adamantinomatous (aCP) and papillary (pCP) (WHO 2021) are distinct entities[1]. They may have a poor prognosis due to their high recurrence rate and anatomical location. The association between surgical procedures and recurrence is well reported, however, a definitive predictive factor for recurrence based on tumor molecular markers has yet to be elucidated. The genetic mutations BRAF V600E and CTNNB1 are mutually exclusive to aCP and pCP respectively and their presence has been well documented (WHO). The expression of molecular markers ki67, p53, VEGF, PD-L1, pATM, RARγ, RARβ, CD166, CD133, E-Cadherins, FABP5, CRAPBII, Vimentins, CXCL12, CXCR4, MCM6 and DNA Topo II alpha have also all been found in populations of craniopharyngiomas, but the level of their expression and proliferation indices have not previously been clearly summarized in the literature as markers of recurrence. Aim: To perform a systematic review of the common genetic and molecular markers found in either adamantinomatous or papillary craniopharyngiomas and assessment of their impact on recurrence rate. Methods: MEDLINE, Embase, PubMed, Cochrane Library and Scopus electronic were searched in December 2022 using a search string with key words “craniopharyngioma”, “adamantinomatous”, “papillary”, “genetic mutation”, “molecular markers” and “recurrence”. The initial search resulted in 1105 studies. These studies were assessed against inclusion and exclusion criteria. Results: The final review included 26 studies that included 905 patients. Ki67, p53, PD-L1, CXCL12, CXCR4, RARγ FABP5, CRABPII, MCM6 and DNA Topo II alpha molecular markers and CTNNB1 and PTTG-1 gene mutations were found to have an association with an increase in recurrence of adamantinomatous craniopharyngiomas, while VEGF, TERTp, pATM, RARβ, CD166, CD133, E-Cadherins and Vimentins were not. Ki67, p53, PD-L1, FABP5, CRABPII, MCM6 and DNA Topo II alpha molecular markers and BRAF and PTTG-1 gene mutations were found to have an association with an increase in recurrence of papillary craniopharyngiomas, while TERTp, pATM were not. The association of other molecular markers and tumour recurrence, despite large scale studies, gave conflicting results. Conclusion: Our systematic review demonstrates that a multitude of molecular markers and genetic mutations are markers of recurrence or worsening clinicopathology. The identification of genetic mutations and expression of molecular markers and their role in the likelihood of recurrence in either adamantinomatous or papillary craniopharyngiomas provides insight into the potential for novel targets in future therapies.

Case Report: Successful Use of BRAF/MEK Inhibitors in Aggressive BRAF-mutant Craniopharyngioma

Although a benign intracranial tumor, craniopharyngioma treatment has always been considered a challenging clinical problem. Recently, BRAF V600E mutation in the pathogenesis of papillary craniopharyngioma (PCP) has been further revealed. Thus, BRAF inhibitors (BRAFi) serve as an applicable treatment for patients with PCP. Two patients with recurrent PCP were treated with combined BRAFi dabrafenib (150 mg, orally twice daily) and MEK inhibitors (MEKi) trametinib (2 mg, orally twice daily). A follow-up exceeding 2 years was conducted. We meticulously scrutinized the treatment's safety and efficacy profiles by delving into existing literature. One patient harboring a solid tumor achieved a complete tumor response devoid of any adverse events and encountered no recurrence over 2 years subsequent to discontinuation. Moreover, within a mere month of commencing targeted therapy, the tumor demonstratedobservable shrinkage. This finding substantiates the considerable potential inherent in targeted therapy for PCP cases marked by the somatic BRAF V600E mutation. Under specific conditions, individuals diagnosed with PCP can attain a complete tumor response following combined treatment with BRAFi/MEKi.

Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance.

Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies. Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively. Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group ( P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB ( P = 0.01). ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.

BRAF–MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas

BackgroundCraniopharyngiomas, primary brain tumors of the pituitary–hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF–MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy.MethodsEligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF–MEK inhibitor combination vemurafenib–cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data.ResultsOf the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events.ConclusionsIn this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF–MEK inhibitor combination vemurafenib–cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.)

Craniopharyngioma-An update on metabolic and cognitive complications and new therapy.

Craniopharyngiomas (CPs) are rare primary brain epithelial tumors arising in the suprasellar region from remnants of Rathke's pouch. About 50% originate at the level of the third ventricle floor, including the hypothalamus (HT). CPs are characterized by a low proliferation rate and symptoms due to mass effect and local infiltration and are managed primarily with surgery and radiotherapy. Gross total removal of a CP will reduce the recurrence rate but increases the risk of HT damage. Today, subtotal resection is the goal and will reduce the risk of HT damage. There are two histological subtypes of CP-adamantinomatous (ACP) and papillary CP (PCP)-that differ in their genesis and age distribution. ACPs are driven by somatic mutations in CTNNB1 gene (encoding β-catenin), and PCPs frequently harbor somatic BRAF V600E mutations. There are also two phenotypes of outcome, the one with a rather good outcome without HT damage and the other with HT damage where recurrent operation with additional cranial radiotherapy results in HT obesity (HO), affecting psychosocial life and cognitive dysfunction. The group with HO suffers from metabolic syndrome, lower basal metabolic rate, and leptin and insulin resistances. There is currently no successful treatment for HO. The group with HT damage suffers from cognitive dysfunction with attention deficits, impaired episodic memory, and processing speed. Diffusion tensor imaging has shown significant microstructural white matter alteration in several areas important for cognition. Recently, complete or partial tumor response was shown to targeted therapy, with BRAF and Mekinist inhibitors for PCPs with BRAF V600E mutation.

Neuroimaging of pediatric tumors of the sellar region-A review in light of the 2021 WHO classification of tumors of the central nervous system.

Sellar/suprasellar tumors comprise about 10% of all pediatric Central Nervous System (CNS) tumors and include a wide variety of entities, with different cellular origins and distinctive histological and radiological findings, demanding customized neuroimaging protocols for appropriate diagnosis and management. The 5th edition of the World Health Organization (WHO) classification of CNS tumors unprecedently incorporated both histologic and molecular alterations into a common diagnostic framework, with a great impact in tumor classification and grading. Based on the current understanding of the clinical, molecular, and morphological features of CNS neoplasms, there have been additions of new tumor types and modifications of existing ones in the latest WHO tumor classification. In the specific case of sellar/suprasellar tumors, changes include for example separation of adamantinomatous and papillary craniopharyngiomas, now classified as distinct tumor types. Nevertheless, although the current molecular landscape is the fundamental driving force to the new WHO CNS tumor classification, the imaging profile of sellar/suprasellar tumors remains largely unexplored, particularly in the pediatric population. In this review, we aim to provide an essential pathological update to better understand the way sellar/suprasellar tumors are currently classified, with a focus on the pediatric population. Furthermore, we intend to present the neuroimaging features that may assist in the differential diagnosis, surgical planning, adjuvant/neoadjuvant therapy, and follow-up of this group of tumors in children.

Characteristics and factors influencing hypothalamic pituitary dysfunction in patients with craniopharyngioma.

Craniopharyngioma is a benign tumor originating from the sellar region. Damages in this area caused by the tumor itself, surgery, or radiotherapy may result in severe hypothalamic-pituitary dysfunction (HPD) and eventually lead to a significant impairment in the long-term quality of life of patients. This study aimed to investigate the characteristics of HPD in patients with adamantinomatous craniopharyngioma (ACP) or papillary craniopharyngioma (PCP) and to identify the factors affecting HPD after surgery. In this single-center retrospective study, a total of 742 patients with craniopharyngioma were included. The neuroendocrine function of these patients before and after surgery was investigated. The differences in hypothalamic-pituitary function between the ACP and PCP groups were compared. The factors influencing the aggravation of HPD after surgery were identified. The median follow-up after surgery was 15 months. Before surgery, the proportion of patients with diabetes insipidus (DI) and hyperprolactinemia in the PCP group was significantly higher than that in the ACP group (P<0.01), and the proportion of patients with adrenocortical hypofunction in the PCP group was significantly lower than that in the ACP group (P=0.03). Most cases of ACP originated in the sellar region, while most cases of PCP originated in the suprasellar region (P<0.01). More patients experienced adenohypophyseal hypofunction, DI, and hypothalamic obesity at postoperative follow-up than at onset in both the ACP and PCP groups (both P<0.01), with a higher increase observed in the ACP group (P<0.01). Older age at CP onset, tumor recurrence or progression, and ACP type were risk factors for postoperative aggravation of HPD in CP patients. Surgical treatment significantly aggravated HPD in both the ACP and PCP groups, but the specific characteristics and risk factors leading to aggravation were different between the two groups.

Adamantinomatous Craniopharyngioma-A rare Tumor arising from remnant of Rathkes pouch

Craniopharyngioma is a rare tumor arising from squamous rests located at any point along the invagination of the primitive stomodeum, Rathke’s pouch, from the nasopharynx to the hypothalamus. 1 There are two peaks in the occurrence of adamantinomatous craniopharyngioma, one in the first to second decade and the other in the fifth decade. They are generally sporadic and their molecular pathogenesis is poorly defined. There are two clinicopathological forms of craniopharyngiomas-papillary squamous type, and adamantinomatous craniopharyngioma. The classical adamantinomatous variant, which affects people of all ages consists of palisading columnar cells that look like ameloblast of embryonic tooth buds. It has poor prognosis when compared to papillary craniopharyngioma. It has an underlying mutation in β-catenin and translocation of the protein to the nucleus, which can be demonstrated by immunohistochemistry.

Current Advances in Papillary Craniopharyngioma: State-Of-The-Art Therapies and Overview of the Literature.

Craniopharyngiomas are commonly classified as low-grade tumors, although they may harbor a malignant behavior due to their high rate of recurrence and long-term morbidity. Craniopharyngiomas are classically distinguished into two histological types (adamantinomatous and papillary), which have been recently considered by the WHO classification of CNS tumors as two independent entities, due to different epidemiological, radiological, histopathological, and genetic patterns. With regard to papillary craniopharyngioma, a BRAF V600 mutation is detected in 95% of cases. This genetic feature is opening new frontiers in the treatment of these tumors using an adjuvant or, in selected cases, a neo-adjuvant approach. In this article, we present an overview of the more recent literature, focusing on the specificities and the role of oncological treatment in the management of papillary craniopharyngiomas. Based on our research and experience, we strongly suggest a multimodal approach combining clinical, endocrinological, radiological, histological, and oncological findings in both preoperative workup and postoperative follow up to define a roadmap integrating every aspect of this challenging condition.

The molecular pathogenesis of craniopharyngiomas.

Research from the last 20 years has provided important insights into the molecular pathogenesis of craniopharyngiomas (CPs). Besides the well-known clinical and histological differences between the subtypes of CPs, adamantinomatous (ACP) and papillary (PCP) craniopharyngiomas, other molecular differences have been identified, further elucidating pathways related to the origin and development of such tumors. The present minireview assesses current knowledge on embryogenesis and the genetic, epigenetic, transcriptomic, and signaling pathways involved in the ACP and PCP subtypes, revealing the similarities and differences in their profiles. ACP and PCP subtypes can be identified by the presence of mutations in CTNNB1 and BRAF genes, with prevalence around 60% and 90%, respectively. Therefore, β-catenin accumulates in the nucleus-cytoplasm of cell clusters in ACPs and, in PCPs, cell immunostaining with specific antibody against the V600E-mutated protein can be seen. Distinct patterns of DNA methylation further differentiate ACPs and PCPs. In addition, research on genetic and epigenetic changes and tumor microenvironment specificities have further clarified the development and progression of the disease. No relevant transcriptional differences in ACPs have emerged between children and adults. In conclusion, ACPs and PCPs present diverse genetic signatures and each subtype is associated with specific signaling pathways. A better understanding of the pathways related to the growth of such tumors is paramount for the development of novel targeted therapeutic agents.

Optic tract edema in craniopharyngioma as a predictor of BRAFV600E mutation presence.

the advent of BRAF inhibitors for preoperative treatment of craniopharyngioma has necessitated the identification of BRAFV600E status. Hence, we investigated predictors of BRAFV600E mutation in craniopharyngiomas. this retrospective study utilized data from 30 patients who were newly diagnosed with craniopharyngioma between 2011 and 2021. Magnetic resonance imaging (MRI) and computed tomography were performed within 1 week prior to surgery. Genetic analysis for BRAF mutation was performed using the Oncomine next-generation sequencing panel or Sanger sequencing. The relationship between BRAF mutation and demographic data, endocrinological function and tumour characteristics on imaging was assessed. tumour tissue carried the BRAFV600E mutation in nine patients. There was no significant difference in age, sex, or presence of hormonal dysfunction amongst patients with and without the BRAFV600E mutation in the tumour. Most tumours with the BRAFV600E mutation were histologically categorized as papillary craniopharyngioma (P=0.0005), and were solid (P=0.0002) and supra-diaphragmatic (P=0.0033) on MRI. BRAFV600E tumours were more frequently associated with optic tract edema than wild-type tumour s (55.6 vs. 0%, P=0.0009) and all tumour s with optic tract edema carried the BRAFV600E mutation. Optic tract edema was not associated with tumour volume, cysts, or preoperative pituitary function. in craniopharyngiomas, the presence of optic tract edema can predict the presence of BRAFV600E mutation with a positive predictive value of 100%. The finding should be verified in larger prospective cohorts and multivariate regression analysis.

Implications of BRAF V600E mutation in gliomas: Molecular considerations, prognostic value and treatment evolution.

Gliomas are molecularly heterogeneous brain tumors responsible for the most years of life lost by any cancer. High-grade gliomas have a poor prognosis and despite multimodal treatment including surgery, radiotherapy, and chemotherapy, exhibit a high recurrence rate. There is a need for new therapeutic approaches based on precision medicine informed by biomarker assessment and BRAF, a key regulator of MAPK signaling pathway, influencing cell differentiation, proliferation, migration and pro-tumorigenic activity, is emerging as a promising molecular target. V600E, is the most frequent BRAF alteration in gliomas, especially in pediatric low-grade astrocytomas, pleomorphic xanthoastrocytoma, papillary craniopharyngioma, epithelioid glioblastoma and ganglioglioma. The possible application of BRAF-targeted therapy in gliomas is continuously growing and there is preliminary evidence of prolonged disease control obtained by BRAF inhibitors in tumors harboring BRAF V600E mutation. The possibility of introducing targeted therapies into the treatment algorithm represents a paradigm shift for patients with BRAF V600E mutant recurrent high-grade and low-grade glioma and BRAF routine testing should be considered in clinical practice. The focus of this review is to summarize the molecular landscape of BRAF across glioma subtypes and the novel therapeutic strategies for BRAF V600E mutated tumors.

Contemporary Biological Insights and Clinical Management of Craniopharyngioma.

Craniopharyngiomas are clinically aggressive tumours due to their invasive behaviour and recalcitrant tendency to recur after therapy. There are two types based on their distinct histology and molecular features: The papillary craniopharyngioma (PCP), which is associated with BRAF-V600E mutations and the adamantinomatous craniopharyngioma (ACP), characterised by mutations in CTNNB1 (encoding β-catenin). Patients with craniopharyngioma show symptoms linked to the location of the tumour close to the optic pathways, hypothalamus and pituitary gland, such as increased intracranial pressure, endocrine deficiencies and visual defects. Treatment is not specific and mostly non-curative, and frequently includes surgery, which may achieve gross-total or partial resection, followed by radiotherapy. In cystic tumours, frequent drainage is often required and intracystic instillation of drugs has been used to help manage cyst refilling. More recently targeted therapies have been used, particularly in papillary craniopharyngioma, but also now in adamantinomatous craniopharyngioma and clinical trials are underway or in development. Although patient survival is high, the consequences of the tumour and its treatment can lead to severe comorbidities resulting in poor quality of life, in particular for those patients that bear tumours with hypothalamic involvement. Accordingly, in these patients at risk for the development of a hypothalamic syndrome hypothalamus-sparing treatment strategies such as limited resection followed by irradiation are recommended. In this review, we provide an update on various aspects of craniopharyngioma, with emphasis on recent advances in the understanding of tumour pathogenesis, clinical consequences, management and therapies.

Current Approaches to Craniopharyngioma Management.

Craniopharyngiomas (CP) are rare noncancerous brain tumors located in the skull base. To date, CP remain challenging-to-resect tumors, owing to their difficult location and invasive potential, with profound adverse effects for the patient if left to grow. Indeed, gross total resection may also be accompanied by unwelcome sequalae, underscoring the need for continued investigation. In the present work, we provide a scoping review of current CP management, with emphasis on our knowledge of their genesis, available treatment options, post-intervention clinical outcomes. Leading theories of CP development are (1) the embryonic theory, explaining the development of adamantinomatous CP from epithelial remnants of Rathke's pouch and (2) the metaplastic theory, which describes papillary CP development as a result of adenohypophyseal cell metaplasia. Treatment may include surgery, intracystic therapy, or irradiation depending on tumor size, history and location. However, whether a single ideal approach and timing for CP intervention exists remains debated. We appraise and critique these areas with priority for emerging basic results and innovation.

Pathological Diagnosis of Adult Craniopharyngioma on MR Images: An Automated End-to-End Approach Based on Deep Neural Networks Requiring No Manual Segmentation.

The goal of this study was to develop end-to-end convolutional neural network (CNN) models that can noninvasively discriminate papillary craniopharyngioma (PCP) from adamantinomatous craniopharyngioma (ACP) on MR images requiring no manual segmentation. A total of 97 patients diagnosed with ACP or PCP were included. Pretreatment contrast-enhanced T1-weighted images were collected and used as the input of the CNNs. Six models were established based on six networks, including VGG16, ResNet18, ResNet50, ResNet101, DenseNet121, and DenseNet169. The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were used to assess the performances of these deep neural networks. A five-fold cross-validation was applied to evaluate the performances of the models. The six networks yielded feasible performances, with area under the receiver operating characteristic curves (AUCs) of at least 0.78 for classification. The model based on Resnet50 achieved the highest AUC of 0.838 ± 0.062, with an accuracy of 0.757 ± 0.052, a sensitivity of 0.608 ± 0.198, and a specificity of 0.845 ± 0.034, respectively. Moreover, the results also indicated that the CNN method had a competitive performance compared to the radiomics-based method, which required manual segmentation for feature extraction and further feature selection. MRI-based deep neural networks can noninvasively differentiate ACP from PCP to facilitate the personalized assessment of craniopharyngiomas.