Tumor Predisposition Syndrome Research Articles

NIMG-31. CASE REPORT: DIAGNOSIS OF AN INFILTRATIVE GLIOMA IN A LI-FRAUMENI SYNDROME PATIENT OBSCURED BY LESION RESPONSIVENESS TO NSCLC TREATMENT

Abstract Li-Fraumeni syndrome is a rare, autosomal dominant disorder linked to germline mutations of the TP53 suppressor gene. Patients with this syndrome are predisposed to various malignancies and a variety of brain tumors to include choroid plexus carcinoma, medulloblastoma, and glioma. We present a 46-year-old woman with a history of Li-Fraumeni syndrome which manifested with multiple systemic malignancies including breast cancer, ovarian teratoma, and leiomyosarcoma. The patient had been undergoing MRI brain surveillance since 2018, which was initially notable for a right cerebellar midline focus of enhancement associated with slowly evolving right middle cerebellar peduncle FLAIR signal, with no detectable neurologic symptoms. She underwent systemic therapy for non-small cell lung cancer (NSCLC) with pemetrexed/cisplatin. Her next MRI brain in August 2023 showed resolution of the cerebellar enhancement with small residual FLAIR signal. In April 2024, the patient presented with new neurologic symptoms to include ataxia, dizziness, difficulty swallowing, and memory loss. Repeat MRI brain revealed new infiltrative FLAIR signal throughout the right temporal lobe extending from the posterior fossa, contiguous with the previously seen cerebellar findings and consistent with infiltrative glioma. Due to fragmented records and care in multiple systems, her updated MRI initially created a diagnostic challenge with a radiographic interpretation of likely encephalitis. This is a unique case documenting a middle-aged female with Li-Fraumeni syndrome, followed for multiple cancers, presenting with new neurologic symptoms and progressive infiltrative FLAIR changes spanning from the cerebellum into the right temporal lobe. These findings highlight the natural history of a TP53 deficient tumor that ostensibly responded to a cisplatin-based regimen given for a different indication, thereby delaying time to symptom onset and need for biopsy. Surveillance of low grade lesions in patients with underlying tumor predisposition syndromes must be interpreted in context of systemic disease burden and concurrent treatments for other neoplasms.

Ependymoma Alongside Hereditary Paraganglioma-Phaeochromocytoma Syndrome Due to a SDHB Mutation: A Case Report

Mutations in the SDHB gene cause a characteristic syndrome that includes paragangliomas (PGL) and phaeochromocytomas (PCC). Herein we present a rare case of an ependymoma in a patient with a germline SDHB mutation. A 41-year-old man with a positive family history of PGL/PCC syndrome was found to have the familial SDHB mutation. Screening imaging for paragangliomas revealed an incidental presumed ependymoma originating from the fourth ventricle. He was followed with serial imaging to assess for progression of the lesion. Due to slow, substantial growth of the tumour, and increasing symptoms which included diplopia, unsteadiness, and wide-based gait, he underwent a resection 5 years after the lesion’s identification. Following resection of the tumour, the pathology confirmed the tumour as a posterior fossa type B (PFB) ependymoma of the fourth ventricle. Unfortunately, on Day 26 post-operatively, the patient had a pulmonary embolism and died. His family consented to an autopsy, which revealed the presence of a clinically-silent pituitary neuroendocrine tumour (PitNET). Though ependymomas are not commonly seen in PGL/PCC syndrome, they can occur. This case represents the first molecularly-characterised ependymal tumour described in this tumour predisposition syndrome. Clinicians ought to be aware of the risk of ependymoma in patients with PGL/PCC syndrome and consider this tumour when conducting their screening and follow-up of asymptomatic SDHx mutation carriers.

Update on surveillance guidelines in emerging Wilms tumor predisposition syndromes.

Wilms tumors are commonly associated with predisposition syndromes. Many of these syndromes are associated with specific phenotypic features and are discussed in the related paper from the AACR Pediatric Cancer Working Group. Guidelines for surveillance in this population were published in 2017 but since then several studies have identified new genes with recurrent pathogenic variants associated with increased risk for Wilms tumor development. In general, variants in these genes are less likely to be associated with other phenotypic features. Recently, members of the AACR Pediatric Cancer Working Group met to update surveillance guidelines for patients with a predisposition to Wilms tumors with a review of recently published evidence and risk estimates. Risk estimates for Wilms tumor for the more recently described genes are discussed here along with suggested surveillance guidelines for these populations. Several other emerging clinical scenarios associated with Wilms tumor predisposition are also discussed including patients with family histories of Wilms tumor and no identified causative gene, patients with bilateral tumors, and patients with somatic mosaicism for chromosome 11p15.5 alterations. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors and other healthcare professionals on emerging evidence and harmonize updated surveillance recommendations in the North American and Australian context for patients with emerging forms of Wilms tumor predisposition.

DICER-1 Mutation Associated Sarcoma of Thyroid in An Adult Male

Abstract Introduction/Objective DICER-1 is an autosomal dominant tumor predisposition syndrome caused by germline DICER1 mutations. In the thyroid, it is associated with an early-onset multinodular goiter (MNG) and low-grade thyroid carcinomas. The aggressive variants thyroblastoma and poorly differentiated carcinoma are however seen in the pediatric age group. We report a case of DICER-1-associated (rhabdomyo) sarcoma without primitive components in an adult male. Methods/Case Report A 44-year-old healthy male with a family history of MNG, presented with a large left neck mass confirmed on imaging with largest 6.4cm, and extension into the mediastinum. FNA showed a malignant spindle cell- rich neoplasm with negative expression for Keratins, TTF-1, PAX-8, Calcitonin, INSM- 1 and SOX-10. The CEA and calcitonin were normal. The lymphoma was excluded by flow cytometry. The patient underwent a left thyroidectomy with central and left selective neck dissection. On gross examination, the left lobe of the thyroid was replaced by a tan- white, partially encapsulated solid mass. Microscopic examination revealed nests and sheets of ovoid to spindle- shaped cells with eosinophilic cytoplasm in fascicles with hypocellular areas with loose stroma. Foci of rhabdomyoblastic differentiation with straps cells, positive for desmin and myogenin were identified. Brisk mitotic activity and tumor necrosis were present. No primitive thyroid epithelium or blastemal component was identified. Tumor cells were negative for S100, SOX10 CD34, CD31, SMA, calponin, CD99, NKX2.2, SS18-SSX which excluded malignant peripheral nerve sheath tumor, angiosarcoma, leiomyosarcoma, Ewing’s sarcoma, and synovial sarcoma. Next-generation sequencing showed a DICER1 c.4517G>A (p.W1506) and c.5437G>C (p.E1813Q) mutation, both variants reported as germ-line variants. A final diagnosis of DICER-1-associated rhabdomyosarcoma was rendered. The patient underwent rehabilitation at another facility and lost to follow-up. Results (if a Case Study enter NA) NA Conclusion The case highlights the expanding spectrum of DICER-1-associated malignant tumors and the importance of keeping it in the differential diagnosis of unusual malignant tumors of the thyroid even in adults.

12396 A Case Of Medullary Thyroid Carcinoma Without Germline RET Mutation

Abstract Disclosure: I. Marranzini Rodriguez: None. M. Lemelman: None. L. Canham: None. Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from the parafollicular C cells of the thyroid gland. MTC accounts for approximately 5% of thyroid cancer in children, and the majority of MTC cases are associated with the autosomal dominant tumor predisposition syndrome Multiple Endocrine Neoplasia 2 (MEN2). Sporadic MTC is uncommon in the pediatric population and associated with somatic mutations of RET or RAS (1). Existing management options for metastatic disease have demonstrated some benefit, however, with systemic side effects. Selpercatinib, a highly selective RET kinase inhibitor, is FDA approved for patients >= 12 years of age. Here we present a case of a 10-year-old patient with metastatic MTC with encouraging results. Clinical Case: A previously healthy 10 year 2-month-old male presented with left-sided neck swelling. Imaging showed a 9.7 cm solid mass spanning nearly the entire left neck, occluding the left internal jugular vein, extending to the upper chest, and resulting in high-grade narrowing of the trachea near the thoracic inlet; the mass involved the left thyroid gland and engulfed the left common carotid. His initial lab evaluation showed an elevated TSH of 10.10 mcU/mL (0.6-5.5 mcU/mL) and Free T4 1.22 ng/dL (0.9-1.67 ng/dL). Tumor markers revealed a calcitonin of 32,264 pg/mL (normal range <= 6.0 pg/mL) and carcinoembryonic antigen (CEA) of 200 ng/ml (normal range 0 – 3.4 ng/mL). He underwent biopsy of the mass which showed medullary thyroid carcinoma (MTC) and genetic evaluation of tumoral tissue showed RET c.2753T>C, p.M918T somatic mutation. Evaluation for pheochromocytoma and hyperparathyroidism, given association of MTC with MEN2, was negative. Genetic testing was negative for germline RET mutations. He was started on selpercatinib, 120 mg every 12 hours. Follow up imaging after 2 months of therapy demonstrated a significant decrease in tumor burden. Approximately 5 months after starting he had a decrease in CEA to 14.8 ng/mL and calcitonin to 69 pg/mL, prior to surgery. Given the risk of locoregional recurrence he underwent total thyroidectomy with lateral neck dissection. However, the tumor was noted to be adherent to the trachea, encasing the left recurrent laryngeal nerve, and left carotid artery preventing full resection. He was started on levothyroxine at 62.5 mcg daily on POD#1 and re-started on selpercatinib approximately 2 weeks post-operatively. Conclusion: We present a case of RET-positive metastatic medullary thyroid carcinoma without germline RET mutation successfully treated with selpercatinib. Long-term follow-up for sustained response and tolerability is needed. Reference: 1. Bauer, Andrew J. “Pediatric Thyroid Cancer: Genetics, Therapeutics and Outcome.” Endocrinology and metabolism clinics of North America vol. 49,4 (2020): 589-611. doi:10.1016/j.ecl.2020.08.00 Presentation: 6/2/2024

Osteosarcoma as a secondary malignancy following rhabdomyosarcoma: A report of 28 affected patients from the Cooperative Osteosarcoma Study Group (COSS).

Osteosarcoma may arise as a secondary malignancy following rhabdomyosarcoma (RMS). We utilized the Cooperative Osteosarcoma Study Group (COSS) database to better understand this association. The COSS database (1980-05/2023) was searched for patients whose osteosarcoma was preceded by RMS. Eligible patients were analyzed for patient-, tumor-, and treatment-related variables as well as outcomes. The search revealed 28 eligible osteosarcomas (27 high-grade central, one periosteal; male:female=16:12; median age RMS 2.1 [range: 0.9-10.0] years, osteosarcoma 13.5 [7.2-29.0] years). Genetic tumor-predisposition syndromes were documented in 12 patients. One patient had had a distinct malignancy prior to RMS, two intermittently, seven following osteosarcoma. Local RMS treatment had included radiotherapy in 20/26 cases (two unknown). Secondary osteosarcoma sites were extremity 13, trunk seven, head and neck eight; 15 osteosarcomas were radiation-associated. There was only one case of primary osteosarcoma metastases. Osteosarcoma treatment included chemotherapy (27), surgery (26), or radiotherapy (2). A macroscopically complete remission of all osteosarcoma sites was achieved in 24 cases. Median follow-up was 5.8 (range: 0.5-18.4) years after osteosarcoma and 8.1 (1.0-15.4) years for 14 survivors. Actuarial 5-year overall and event-free survival were 66% (standard error 9%) and 45% (10%), respectively. Five of 14 deaths were caused by further malignancies. This series offers a benchmark for patients who develop a secondary osteosarcoma after RMS. Affected patients are generally still in the pediatric age. The results obtained strongly argue for genetic predisposition testing in RMS and against therapeutic leniency in comparable situations.

BRCA1-associated-protein-1 inactivated melanocytic tumours: characterisation of the clinicopathological spectrum and immunohistochemical expression pattern of preferentially expressed antigen in melanoma.

BRCA1-associaed protein-1 (BAP1) inactivated tumours (BIMT) are rare melanocytic tumours that may be mistaken for Spitz tumours or melanoma. They occur sporadically or in association with the BAP1 tumour predisposition syndrome (BAP1-TPDS), which may be complicated by uveal or cutaneous melanoma, mesothelioma, basal cell carcinoma and renal cell carcinoma. The aim of this study was to characterise the clinicopathological features and the immunohistochemical expression pattern of preferentially expressed antigen in melanoma (PRAME) of BIMT in a large patient cohort. Ethical approval was obtained, haematoxylin and eosin-stained slides were reviewed, PRAME immunohistochemistry was performed and clinical follow-up was obtained from patient records. Sixty-five BIMT from 38 patients (F:M = 4.4:1) were identified. BIMT were typically located on the trunk and head and neck (median size = 0.5 cm). Seven patients with BAP1-TPDS (range = 16-66 years, median = 25) had multiple BIMT (median = 5), while sporadic BIMT were solitary (median patient age = 39 years). One of seven patients with BAP1-TPDS developed additional malignancies (mesothelioma and cutaneous spindle cell melanoma) and died of complications of mesothelioma. All other patients are alive without recurrence of BIMT (median follow-up = 42 months). BIMT presented as intradermal, nodular aggregates of epithelioid melanocytes with low mitotic activity and moderate to severe cytological atypia in 63% of cases. A background conventional naevus was present in 64%. PRAME immunohistochemistry showed negative or weakly patchy positive staining in all BIMT. BIMT are more common in a sporadic setting and behave indolently, despite worrying cytological atypia. PRAME immunohistochemistry is a reassuring tool in distinguishing BIMT from melanoma.

Neurofibromatosis type1 adult surveillance form for Austria.

Neurofibromatosis type1 (NF1) is arare autosomal dominant tumor predisposition syndrome with abirth prevalence of approximately 1in 2000-3000 individuals. Management of both benign and malignant tumors arising in individuals with NF1 is demanding and tumors may be difficult to treat. Both standardized and individual surveillance programs are therefore highly important to prevent morbidity and mortality in patients with NF1. The guidelines for the clinical management of NF1 recently proposed by the European Reference Network for Genetic Tumor Risk Syndromes provide the cornerstone of the present surveillance form and were discussed through three rounds of voting and afinal consensus meeting involving experts from five Austrian and one German clinical NF1 centers for adults and one patient organization representative. Subsequently, 31items within 4categories were integrated into the proposed surveillance form for Austria. All recommendations, unless otherwise specified, pertain to primarily asymptomatic patients in routine follow-up. At healthcare transition from pediatric to adult surveillance or the initial visit in adulthood, we suggest athorough clinical, laboratory and radiological examination to obtain abaseline for future diagnostics. To comply with the general screening recommendations in Austria, we suggest extending the frequency of clinical visits from annual to biennial at 50years of age. In cases of clinical dynamics, early follow-up is recommended to facilitate early detection of potential complications. Particular emphasis should be placed on preventive patient education.

Practical Approach to Congenital Anomalies of the Kidneys: Focus on Anomalies With Insufficient or Abnormal Nephron Development: Renal Dysplasia, Renal Hypoplasia, and Renal Tubular Dysgenesis.

Congenital anomalies of the kidney and urinary tract (CAKUT) accounts for up to 30% of antenatal congenital anomalies and is the main cause of kidney failure in children worldwide. This review focuses on practical approaches to CAKUT, particularly those with insufficient or abnormal nephron development, such as renal dysplasia, renal hypoplasia, and renal tubular dysgenesis. The review provides insights into the histological features, pathogenesis, mechanisms, etiologies, antenatal and postnatal presentation, management, and prognosis of these anomalies. Differential diagnoses are discussed as several syndromes may include CAKUT as a phenotypic component and renal dysplasia may occur in some ciliopathies, tumor predisposition syndromes, and inborn errors of metabolism. Diagnosis and genetic counseling for CAKUT are challenging, due to the extensive variability in presentation, genetic and phenotypic heterogeneity, and difficulties to assess postnatal lung and renal function on prenatal imaging. The review highlights the importance of perinatal autopsy and pathological findings in surgical specimens to establish the diagnosis and prognosis of CAKUT. The indications and the type of genetic testing are discussed. The aim is to provide essential insights into the practical approaches, diagnostic processes, and genetic considerations offering valuable guidance for pediatric and perinatal pathologists.

Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.

Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5-8% of all kidney cancer cases and is associated with syndromes such as von Hippel-Lindau syndrome, Birt-Hogg-Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available.

Rapid postradiation malignant transformation of a pilocytic astrocytoma in an adult with neurofibromatosis type 1: illustrative case.

Juvenile pilocytic astrocytoma (JPA) is the most common primary brain tumor of childhood and is rarely seen in adults. Neurofibromatosis type 1 (NF1), a common tumor predisposition syndrome, demonstrates a strong association with low-grade gliomas, most notably pilocytic astrocytoma, which are relatively indolent. Unlike its juvenile counterpart, reports of adult pilocytic astrocytoma (APA) vary widely in terms of disease progression from benign to much more malignant courses. Moreover, current studies discussing APA report different treatment approaches and outcomes (e.g., malignant transformation of JPA and APA with or without radiation), as little is known regarding the management of recurrent tumors and how adjuvant therapies may alter disease progression. The authors report the unique case of an adult male with NF1 and APA who underwent rapid malignant conversion after intensity-modulated radiation therapy. The authors demonstrate that caution should be taken in utilizing radiotherapy instead of resection in cases of APA and NF1, with close monitoring for posttreatment recurrence. https://thejns.org/doi/10.3171/CASE24241.

Late-onset tumors in rhabdoid tumor predisposition syndrome type-1 (RTPS1) and implications for surveillance.

Rhabdoid tumor predisposition syndrome type-1 (RTPS1) is characterized by germline pathogenic variants in SMARCB1 and development of INI1-deficient rhabdoid tumors in early childhood. Due to its poor prognosis, the risk of subsequent tumor development and the impact of surveillance at later ages are poorly understood. We retrospectively reviewed individuals referred to the Cancer Genetics Program at The Hospital for Sick Children for SMARCB1 genetic testing and/or surveillance for RTPS1. In addition, to explore characteristics of late-onset tumors in RTPS1, a literature review was conducted. Of eighty-three individuals (55 probands and 28 family members), 12 probands and 4 family members were genetically confirmed with RTPS1. Four pediatric probands with RTPS1 underwent surveillance. An additional three individuals, including one patient with 22q11.2 distal deletion without history of tumor, one patient with negative genetic testing results but clinically diagnosed with RTPS1, and one sibling identified through cascade testing, underwent surveillance. Three patients with RTPS1 developed tumors between the ages of 9 and 17, including malignant rhabdoid tumors (N = 3), schwannomas (N = 4), and epithelioid malignant peripheral nerve sheath tumor (N = 1). Three of these lesions were asymptomatically detected by surveillance. A literature review revealed 17 individuals with RTPS1 who developed INI1-deficient tumors after age five. Individuals with RTPS1 remain at elevated risk for developing INI1-deficient tumors after the peak age of rhabdoid tumor in early childhood. Extension of surveillance beyond 5 years of age could lead to improved survival and reduced morbidity for these patients, and prospective evaluation of revised approaches will be important.

SMARCA4-deficient primary bone sarcoma with "teratoid" features in a rhabdoid tumor predisposition syndrome patient.

SMARCA4-deficient primary bone sarcoma with "teratoid" features in a rhabdoid tumor predisposition syndrome patient.

Malignant Rhabdoid Tumor and Related Pediatric Tumors: Multimodality Imaging Review with Pathologic Correlation.

Malignant rhabdoid tumors (MRTs) are rare but lethal solid neoplasms that overwhelmingly affect infants and young children. While the central nervous system is the most common site of occurrence, tumors can develop at other sites, including the kidneys and soft tissues throughout the body. The anatomic site of involvement dictates tumor nomenclature and nosology. While the clinical and imaging manifestations of MRTs and other more common entities may overlap, there are some site-specific distinctive imaging characteristics. Irrespective of the site of occurrence, somatic and germline mutations in SMARCB1, and rarely in SMARCA4, underlie the entire spectrum of rhabdoid tumors. MRTs have a simple and remarkably stable genome but can demonstrate considerable molecular and biologic heterogeneity. Related neoplasms encompass an expanding category of phenotypically dissimilar (nonrhabdoid tumors driven by SMARC-related alterations) entities. US, CT, MRI, and fluorodeoxyglucose PET/CT or PET/MRI facilitate diagnosis, initial staging, and follow-up, thus informing therapeutic decision making. Multifocal synchronous or metachronous rhabdoid tumors occur predominantly in the context of underlying rhabdoid tumor predisposition syndromes (RTPSs). These autosomal dominant disorders are driven in most cases by pathogenic variants in SMARCB1 (RTPS type 1) and rarely by pathogenic variants in SMARCA4 (RTPS type 2). Genetic testing and counseling are imperative in RTPS. Guidelines for imaging surveillance in cases of RTPS are based on age at diagnosis. ©RSNA, 2024 Supplemental material is available for this article.

Trigeminal nerve hemangioblastoma in the setting of undiagnosed von Hippel-Lindau disease: illustrative case.

Von Hippel-Lindau disease (VHL) is an autosomal dominant tumor predisposition syndrome caused by mutations in the VHL gene. Patients with VHL are predisposed to developing numerous neoplasms, including central nervous system hemangioblastomas that typically arise within the cerebellum, brainstem, or spinal cord. The authors present the unusual case of a 69-year-old patient with a hemangioblastoma of the trigeminal nerve as his initial presentation of VHL. A 69-year-old male presented with progressive right-sided V3 paresthesias, gait disturbance, and diplopia. Magnetic resonance imaging demonstrated an enhancing 0.5-cm nodule within the right trigeminal nerve and an associated peritumoral cyst exerting mass effect on the cerebral peduncle. Neural axis imaging demonstrated pia-based enhancing lesions concerning for multiple spinal hemangioblastomas. The patient underwent an uncomplicated retrosigmoid craniotomy for trigeminal nerve hemangioblastoma resection. The patient had postoperative improvement in his gait, diplopia, and facial paresthesias. Genetic testing revealed that the patient was heterozygous for a pathological mutation in the VHL gene. Hemangioblastomas in adults over 50 years of age should prompt a workup for VHL. Recognizing that cranial nerves are a possible site of hemangioblastoma occurrence is important for neurosurgeons and radiologists alike. Resection of cranial nerve hemangioblastomas is technically challenging but can lead to symptom improvement for patients. https://thejns.org/doi/10.3171/CASE24149.

Maternal obesogenic diet operates at the tumor cell of origin to increase incidence and decrease latency of Neurofibromatosis Type 1 optic pathway glioma.

Pediatric low-grade glioma incidence has been rising in the U.S., mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the U.S. is largely driven by diet, given the prevalence of high fat and high sugar (HFHS) food choices. Since high-fat diet exposure can increase embryonic neuroglial progenitor cell (NPC) proliferation, the potential cells of origin for low-grade glioma, we hypothesized that in utero exposure to an obesogenic diet would modify pediatric brain penetrance and latency by affecting the tumor cell of origin. We employed several murine models of the Neurofibromatosis type 1 (NF1) pediatric brain tumor predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the embryonic third ventricular zone (TVZ). We exposed dams and offspring to an obesogenic HFHS diet or control chow and analysed fetal neurodevelopment at E19.5 and tumor formation at 6w-3mo. Progeny from HFHS diet-exposed dams demonstrated increased TVZ NPC proliferation and glial differentiation. Dietary switch cohorts confirmed that these effects were dependent upon maternal diet, rather than maternal weight. Obesogenic diet (Ob) similarly accelerated glioma formation in a high-penetrance Nf1-OPG strain and increased glioma penetrance in two low-penetrance Nf1-OPG strains. In contrast, Ob exposure in the postnatal period alone did not recapitulate these effects. These findings establish maternal obesogenic diet as a risk factor for murine Nf1-OPG formation, acting in part through in utero effects on the tumor cell of origin.

Current state of spinal nerve sheath tumor management and future advances.

Nerve sheath tumors are the most common tumors of the spine after meningiomas. They include schwannomas, neurofibroma, and malignant peripheral nerve sheath tumors. These can arise sporadically or in association with tumor predisposition syndromes, including neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Though surgery is the traditional mainstay of treatment for these tumors, the discovery of the genetic and molecular basis of these diseases in recent decades has prompted investigation into targeted therapies. Here, we give a clinical overview of spinal nerve sheath tumors, their imaging features, current management practices, and explore ongoing advances in systemic therapies.

Pathological Diagnosis and Genetic Alterations of Meningioma

Meningiomas, renowned for their histological diversity, are one of the most prevalent brain tumors. Some meningiomas show unusual histomorphology, especially in intraoperative rapid diagnosis. Therefore, clinical and radiological information is crucial for pathological diagnosis. Before the 2021 World Health Organization Classification of Tumors of the Central Nervous System(5th edition), pathological diagnosis relied solely on histopathological features. However, this classification introduced new diagnostic criteria for anaplastic meningiomas, which now include TERT promoter mutations and the homozygous deletion of CDKN2A/B, indicating the necessity of genetic analysis. Some rhabdoid and papillary meningiomas have BAP1 alterations, which tend to demonstrate an aggressive clinical course and may represent a phenotype of BAP1-related tumor predisposition syndrome. Heterozygous deletion of CDKN2A/B and loss of H3 p.K28me3(K27me3)are also associated with poor prognosis. Although some immunohistochemical markers like MTAP may serve as surrogates for the homozygous deletion of CKKN2A/B, genetic analysis is required to confirm TERT promoter mutations. Therefore, in routine clinical practice, neurosurgeons and pathologists prioritize appropriate formalin fixation to facilitate genetic analysis using pathological specimens.

SG13 Managing cutaneous manifestations of FH-associated tumour predisposition syndrome: a systematic review of case reports

SG13 Managing cutaneous manifestations of FH-associated tumour predisposition syndrome: a systematic review of case reports

Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors

BackgroundNF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors.MethodsIn this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes.ResultsA total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (−0.013 units per month; 95% CI, −0.002 to −0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported.ConclusionsBrigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children’s Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.)