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RARE-49. CHOROID PLEXUS ADENOMA WITHOUT ASSOCIATED HYDROCEPHALUS PRESENTING AS PRECOCIOUS PUBERTY

Abstract Precocious puberty (PP) is a rare presentation of intracranial pathology unrelated to the pituitary. PP in this setting is considered a paraneoplastic phenomenon, achieved through synthesis of sex-hormones by the tumor itself or via alterations in the release of gonadotrophins from the pituitary. The latter has been described with masses adjacent to the pituitary or with those which cause hydrocephalus. We describe a case of a choroid plexus papilloma (CPP) without hydrocephalus presenting as precocious puberty. An 18 month-old female presented with 4-months of weight loss, bilateral galactorrhea and constipation. Her weight decreased from the 15th to below the 1st percentile. CBC, celiac and thyroid studies were normal. Prolactin was at the upper limit of normal (25.8;ref 3.3–26.3). Breast ultrasound demonstrated symmetric breast tissue development. She was referred to pediatric gastroenterology for constipation and failure to thrive. Caloric supplementation, bowel regimen and barium enema were recommended. One week later, she was admitted with dehydration, painful constipation and further weight loss in the setting of an acute febrile illness. MRI revealed a normal pituitary and an intraventricular mass without hydrocephalus. She underwent gross total resection of the mass, later determined to be a choroid plexus papilloma. The patient’s galactorrhea resolved abruptly following resection. Because of her galactorrhea, our patient underwent neuroimaging revealing an incidental mass without associated hydrocephalus. To our knowledge, precocious puberty and hyperprolactinemia have not been described in neoplasms distant from the pituitary. Thus, these lesions should be recognized as a potential etiology of precocious puberty and hyperprolactinemia.

Pediatric chordomas are exceedingly rare and there are limited data to guide treatment decisions. We report a retrospective analysis of 19 patients with chordomas who received treatment at our institution from 2001-2020. Of the 19 patients, 15 had clival (79%), 3 cervical and 1 sacral chordoma. There were 9 males (47%). Median age at diagnosis of 10.6 years. Eight patients had gross total (42%) and 11 (58%) had sub-total resection. As front line therapy 15 patients (79%) underwent surgery followed by radiation (1 photon and 14 proton), 3 patients (16%) received surgery and chemotherapy (anaplastic histology) and 1 patient received only surgery. For patients treated with radiation therapy the average prescribed dose was 70 Gy (range: 52-74). Post-surgery and radiation, 14 of 15 patients remained in remission. Five (26%) patients had progressive disease (PD) with median time to progression of 13 months of whom 3 died of disease at median of 18 months. Treatment of PD consisted of chemotherapy and radiation for 3, re-resection with radiation for 1 and chemotherapy alone for 1 patient. The patients with metastatic and anaplastic disease mean survival is 21 month versus 45 for the rest of the cohort. In summary, post-operative adjuvant radiation provided an overall good outcome in majority of patients. Patients with anaplastic pathology and metastasis at diagnosis had worse outcome. Those who relapsed, subsequent treatment was palliative at best with short survival. Molecular analysis is warranted in future for better disease stratification.

RARE-45. SARCOMAS INVOLVING THE CENTRAL NERVOUS SYSTEM AT INITIAL PRESENTATION IN CHILDREN AND YOUNG ADULTS: A CASE SERIES
Yen-Lin Liu 1,2 , Shu-Mei Chen 2 , Hsin-Lun Lee 2,3 , Jia-Hui Huang 2 , Shu-Huey Chen 1,4 , Yu-Chien Kao 1,4 , Hsi Chang 2 , Min-Lan Tsai 2 , Sung-Hui Tseng 2 , Kevin L.C. Hsieh 2 , Chia-Yau Chang 2 , Jinn-Li Wang 1,5 , James S. Miser 1,6 , and Tai-Tong Wong 2 ; 1 Taipei Medical University, Taipei, Taiwan, 2 Taipei Medical University Hospital, Taipei, Taiwan, 3 Taipei Cancer Center, Taipei, Taiwan, 4 Shuang Ho Hospital, New Taipei, Taiwan, 5 Taipei Municipal Wan Fang Hospital, Taipei, Taiwan, 6 City of Hope, Duarte, CA, USA Sarcomas of bone, soft tissue, or neural origin may occasionally invade the central nervous system (CNS), causing diagnostic and therapeutic challenges. We aim to investigate the clinical features of sarcomas involving the CNS at initial presentation. During 2015/01-2019/12, nine consecutive patients (4 Males and 5 Females) younger than 30 years of age treated at a University Healthcare System in Northern Taiwan were included. The median age was 8.7 years (range, 2-24 years); diagnoses were Ewing Sarcoma with EWSR1 rearrangements (n=4), CIC-NUTM1 Sarcoma (n=1), Osteosarcoma (n=2), Malignant Peripheral Nerve Sheath Tumor (MPNST; n=1), and extramedullary myeloid sarcoma (n=1). The tumors originated from the skull (n=1), dura (n=1), vertebra (n=4), spinal canal (n=1), or extra-CNS sites (n=2). Four patients had metastases (1 Ewing sarcoma, 2 osteosarcoma, and 1 extramedullary myeloid sarcoma). The main symptom at diagnosis was facial/ eye pain (n=2), back pain (n=3), arm weakness (n=1), or gait disturbance (n=3). Upfront neurosurgical decompression (n=7) or urgent radiotherapy (n=1) was performed in most patients. At a median follow-up duration of 20.1 months, the overall survival rate was 70%. All patients with Ewing sarcoma (n=4) and CIC-NUTM1 sarcoma (n=1) achieved Complete Response after surgery, interval-compressed chemotherapy, radiotherapy, and adjuvant chemotherapy. Patients with stage IV osteosarcoma (n=2) had Partial Response; the patients with MPNST and extraskeletal myeloid sarcoma died of Progressive Disease at 18 and 3 months after diagnosis, respectively. We conclude that timely decompression, early diagnosis, and histology-driven multimodality treatment are effective strategies in managing sarcomas involving the CNS. In 2006 we reported the youngest case of a large clival chordoma, a 15-week old baby, the second case to present without skull base involve-ment and the fourth case of chordoma in a patient with tuberous sclerosis. This unusually rare case (surgically un-resect able) underwent endoscopic skull-base diagnostic biopsy and a novel chemotherapy regime that aimed to control his disease [i]. Initial tumour control was achieved with chemotherapy (Ifosfamide, doxorubicin with dexrazonane, intrathecal hydrocortisone, methotrexate, cytarabine). Carboplatin and etoposide were later given for a further year. Following this, Sirolimus and imatinib were used for another twelve months due to primary tumour regrowth and three new skull-vault lesions. Sirolimus alone was continued for an additional year, but stopped due to optic neuritis. Imatinib was given until further progression two years later, leading to a change to everolimus. Surgery for the ventral foramen magnum was performed a year later. The patient received further surgery and radiotherapy for tumour recurrence. Sadly the tumour metastasised and he succumbed at age 13. Chordomas are aggressive and recur frequently. Complete primary resection followed by radiotherapy/proton beam therapy offers the best chance of cure but is not an option in infants with giant lesions, as in our case. We inform on alternative targeted treatment strategies and review the literature on these rare lesions. Diffuse leptomeningeal disseminated glioneuronal tumor (DL-GNT) is a rare brain tumor that presents as a plaque-like subarachnoid tumor, commonly involving the basal cisterns and interhemispheric fissure of children but lacking intraparenchymal tumor. Here we report two cases focusing on clinicopathologic features. In all patients, radiography revealed characteristic leptomeningeal thickening and enhancement with minor superficial parenchymal lesions. The broadcast of the knowledge about this type of disease is important to increase awareness on this subject.

RARE-48. CHARACTERISTICS AND OUTCOME OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT): A SINGLE INSTITUTION EXPERIENCE
Emily Owens Pickle, Ana Aguilar-Bonilla, and Amy Smith; Arnold Palmer Hospital for Children, Orlando, FL, USA Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare with an unknown etiology and unestablished incidence. Most frequently reported genetic alteration is KIAA1549-BRAF fusion. We present four DLGNT cases diagnosed between 2005-2018. Patient 1 is a female who presented with a 2-year history of back pain subsequently diagnosed with pilocytic astrocytoma. Re-imaging 3 months post-resection revealed a low grade glioneuronal tumor with BRAF duplication. Patient 2 is a female who presented with recurrent vomiting, dizziness, and hydrocephalus. The patient underwent biopsy which was consistent with oligodendrogliomatosis; no genetic analysis was done. Patient 3 is a male who presented with worsening headaches and intermittent vomiting. Approximately 5 months after resection, imaging showed leptomeningeal disease and further testing revealed KIAA1549-BRAF fusion and 1p deletion. Patient 4 is a male who presented with hydrocephalus. Imaging showed disseminated leptomeningeal enhancement without a dominant mass lesion; biopsy and clinical history confirmed the diagnosis. All four patients received chemotherapy, Patients 1 and 3 underwent radiation therapy, and Patient 3 received a MEK-inhibitor to which he had a great response. However, the patient was non-compliant and had PD which continued despite re-starting therapy. Patients 1, 2, and 3 have died of progressive disease; survival was Patient 1, 276 days, Patient 2, approximately 7 years and 8 months, and Patient 3, 2 years and 11 months. Patient 4 remains alive with disease 4.5 years from diagnosis. There is much to be learned about this rare, poorly understood disease but hope for improvement through therapeutic targeting of the MAPK pathway.

RARE-49. CHOROID PLEXUS ADENOMA WITHOUT ASSOCIATED HYDROCEPHALUS PRESENTING AS PRECOCIOUS PUBERTY
Kaylyn Utley, Michael Dedekian, James Wilson, and Stanley Chaleff; Maine Medical Center, Portland, ME, USA Precocious puberty (PP) is a rare presentation of intracranial pathology unrelated to the pituitary. PP in this setting is considered a paraneoplastic phenomenon, achieved through synthesis of sex-hormones by the tumor itself or via alterations in the release of gonadotrophins from the pituitary. The latter has been described with masses adjacent to the pituitary or with those which cause hydrocephalus. We describe a case of a choroid plexus papilloma (CPP) without hydrocephalus presenting as precocious puberty. iii453

NEURO-ONCOLOGY • December 2020
An 18 month-old female presented with 4-months of weight loss, bilateral galactorrhea and constipation. Her weight decreased from the 15th to below the 1st percentile. CBC, celiac and thyroid studies were normal. Prolactin was at the upper limit of normal (25.8;ref 3.3-26.3). Breast ultrasound demonstrated symmetric breast tissue development. She was referred to pediatric gastroenterology for constipation and failure to thrive. Caloric supplementation, bowel regimen and barium enema were recommended. One week later, she was admitted with dehydration, painful constipation and further weight loss in the setting of an acute febrile illness. MRI revealed a normal pituitary and an intraventricular mass without hydrocephalus. She underwent gross total resection of the mass, later determined to be a choroid plexus papilloma. The patient's galactorrhea resolved abruptly following resection. Because of her galactorrhea, our patient underwent neuroimaging revealing an incidental mass without associated hydrocephalus. To our knowledge, precocious puberty and hyperprolactinemia have not been described in neoplasms distant from the pituitary. Thus, these lesions should be recognized as a potential etiology of precocious puberty and hyperprolactinemia.
Malignant transformation of CPP is rare and the mechanisms remain elusive. We report a case of progression of papilloma into carcinoma where we performed molecular sequencing of both samples. A boy was found to have a brain mass soon after birth. The gross total resection (GTR) was diagnostic of CPP. Six years later he developed a recurrent mass that demonstrated progression to a choroid plexus carcinoma (CPC). The patient received chemotherapy according to a "HeadStartII" protocol. He is 2.5 years off therapy and disease-free. A sequencing study consisting of 1700 genes and tumor transcriptome was done. The analysis of both samples revealed a germline variant of TP53(R248W) with LOH and an allele frequency of 39% in the germline sample, suggesting a mosaicism. Analysis of both samples identified extensive aneuploidy and similar pattern of gains in chromosomes 7/8/12/20/21/X. Copy number aberrations newly acquired in the carcinoma included copy gain of chromosomes 5q/12/15q/20, and copy loss of chromosomes 5q/13/22. The papilloma was found to harbor 3 somatic mutations with 4% to 21% allelic fractions, all lost in the carcinoma. These mutations were of unknown significance and with too low allelic fractions to be responsible for the transformation. More pertinently, chromosomal aneuploidy was significant with additional losses in the carcinoma. This resulted in the losses of two critical tumor suppressor genes, RB and BRCA2, playing a possible role in the observed transformation. The "HeadStart" experience suggested that the prognosis of TP53 mutant CPC may be improved in the absence of radiation therapy.

RARE-52. RB1 GENE DELETIONS ARE THE NOVEL MECHANISM OF CHOROID PLEXUS TUMORS (CPT) ONCOGENESIS
Alexander Druy 1,2 , Liudmila Yasko 1 , Andge Valiakhmetova 1 , Galina Novichkova 1 , and Liudmila Papusha 1 ; 1 D. Rogachev National Medical Research Center, Moscow, Russian Federation, 2 Research Institute of Medical Cell Technologies, Yekaterinburg, Russian Federation BACKGROUND: CPTs are known to be rare TP53-dependent neoplasms, while major molecular alterations underlying tumor progression, especially in TP53-wild type cases, are still unclear. METHODS: 18 primary CPT, including 16 choroid plexus carcinomas (CPC) and two atypical choroid plexus papillomas (CPP), were evaluated for copy number status of 87 major oncogenes and tumor suppressor genes by nCounter Cancer CNV assay by Nanostring and TP53 and RB1 by MLPA. Germline TP53 nucleotide substitutions were analyzed by Sanger sequencing. RESULTS: Pathogenic germline TP53 variants were present in 4 cases confirming Li-Fraumeni syndrome (LFS). Two patients have somatic TP53 substitutions. Only one patient with LFS harbored somatic TP53 deletion. In 7 patients, heterozygous deletions of RB1 involving from 3 exons to the whole coding sequence detected by MLPA were discovered. All these findings were validated by nCounter CNV assay. Additionally, four patients have WT1 deletions, two patients -BRCA2, and in 1 case -NF1, concomitant with RB1 deletions in 3 cases. Interestingly, in one patient who faced a progression of CPP to CPC germline, RB1 deletion was detected, and in both subsequent tumors, the length of the deleted region progressively increased. Notably, that RB1 deletions are mostly mutually exclusive to TP53 substitutions. 3 of 4 patients with RB1 deletions having follow-up period >1 year faced with tumorrelated adverse events. CONCLUSIONS: Somatic or uncommon germline RB1 heterozygous deletions have been unraveled as a novel mechanism of aggressive CPT and could be implemented in prognosis definition schemes.

RARE-53. PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE DIFFERENTIATION (PPTID) AND DICER1 SYNDROME: A CASE REPORT
Stephanie Toll 1,2 , Avanti Gupte 1 , Sandeep Sood 3 , William Kupsky 3 , Deniz Altinok 1,3 , Steven Miller 3 , and Kanta Bhambhani 4,3 ; 1 Children's Hospital of Michigan, Detroit, MI, USA, 2 Central Michigan University, Mount Peasant, MI, USA, 3 Wayne State University, Detroit, MI, USA, 4 Children's Hospital of Michigan, Detroit, USA BACKGROUND: DICER1 syndrome is a rare inherited tumor predisposition syndrome linked to an increased risk of several malignancies. Affected individuals most commonly develop pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors. Brain tumors in these patients are rare, however; the increased frequency of pineoblastoma in this population has been established. Traditionally, pineal parenchymal tumors of intermediate differentiation (PPTIDs) have not been associated with DICER1 syndrome, with research suggesting alternative mutations driving tumorigenesis. These tumors are pathologically and clinically diverse, with long-term surveillance based on therapeutic interventions. Here we describe a case of a germline DICER1 mutation in a patient with a PPTID, suggesting that this mutation is not limited to pineoblastoma as previously reported. CASE: We describe a 19 year-old female with a WHO grade III PPTID treated with multimodal therapy including surgery, craniospinal irradiation (CSI) and chemotherapy. She was noted to have a thyroid mass at diagnosis and was subsequently diagnosed with a benign thyroid nodule, followed most recently by a cataract with pathology concerning for medulloepithelioma of the ciliary body. Due to the known association between medulloepithelioma and DICER1 syndrome, targeted germline sequencing was obtained and confirmed a pathogenic heterozygous mutation. CONCLUSION: To our knowledge this