1. Patient Case Presentation Neurosurgery Red Service Gabriel Zada, MD Sean McNatt, MD LAC-USC Medical Center May 3, 2006

2. Patient J.A. History of Present Illness: –22 month old female I –Irritability, nausea/vomiting, decreased p.o. intake for 6 days prior to admission –Low grade fever per parents –Multiple visits to emergency room + clinics over last week, got intravenous fluids and parents told her illness was viral

3. History of Present Illness (continued): –Presented again to Pediatrics ER with lethargy, altered mental status –Bradycardic to pulse of 70s, hypertensive –Intubated and sedated in ER for airway protection –No recent seizures, no sick contacts Past Medical History: –Past medical and surgical history unremarkable –Term birth, uncomplicated –Normal developmental milestones Patient J.A.

4. Physical Exam: –Patient intubated, sedated –Somnolent but arousable –Regards examiner, not following commands –Pupils briskly reactive and equal –Extraocular movements intact –Tone normal –Moving all extremities with full power –Normocephalic, no external signs of trauma Patient J.A.

5. CT Imaging

27. Initial Management Patient admitted to Neurosurgical ICU Right ventriculostomy placed Initial ICPs in the 20s, normalized with drainage CSF yellow, proteinaceous High ventriculostomy output (150 cc/12 hours) Patient transferred to CHLA for definitive management

28. MRI Brain

65. MR Spectroscopy

67. Operative Management Right parieto-occipital craniotomy Intraoperative ventriculostomy used to cannulate ventricle Gross Total Resection

68. Choroid Plexus Tumors: Epidemiology Comprise 0.5% of all brain neoplasms Comprise 6% of primary pediatric neoplasms 45% occur within the first year of life 70% occur within first 2 years of life Median age at diagnosis is 3.5 years 1.2 : 1 male to female ratio Location: –50% in lateral ventricles –37% in 4 th ventricle –9% in third ventricle –Remainder in other locations

69. Most present with hydrocephalus secondary to CSF overproduction (78-95%) Tumor hemorrhage found in 2 of 21 patients, in one study Most common symptoms: –Nausea,vomiting –Irritability –Headaches –Visual changes –Seizures Most common signs: –Craniomegaly –Papilledema –Stupor or coma in 25% of presentations Choroid Plexus Tumors: Clinical presentation

70. Believed to arise spontaneously Many tumors demonstrated to harbor chromosomal aberrations (usually chromosome 22) CPP has been linked experimentally to the SV40 DNA primate virus Large T antigen is the major regulator of the SV40 virus protein products, and interacts with the product of the p53 and RB tumor suppressor genes When expressed in mice, T antigen induces formation of CPPs Choroid Plexus Tumors: Pathophysiology

71. Choroid Plexus Papilloma: Pathology “Cauliflower-like” appearance Evidence of prior hemorrhage often observed Tumor surface is frond-like, similar to normal choroid plexus Stroma has a fibrous consistency Can differentiate CPP from papillary ependymoma based on histology: –Ependymoma has stroma composed of neuroglia and epithelial cells with cilia Immunohistochemistry not extremely helpful for these lesions

72. Choroid Plexus Carcinoma: Pathology 29-39% of choroid plexus neoplasms are carcinoma Differentiating features: (per WHO criteria) –Nuclear atypia, N/C ratio, mitotic figures –Loss of normal papillary architecture –Invasion of brain parenchyma through ependyma Immunohistochemistry with higher Ki67 index labeling Variant of CPP with stromal invasion ??? –Branching papillae with thin-walled, ectactic blood vessels –More complex architecture than standard CPPs

73. Choroid Plexus Tumors: Pathology Choroid Plexus Papilloma - Normal papillary architecture -Columnar + Cuboidal cells -Single layer stalks Choroid Plexus Carcinoma - Piled up epithelium -Loss of papillary architecture

74. Study by M Levy et al, Neurosurgery, 2001 Many other series of CPCs have a wide variability in survival times and outcomes Variant of (benign) CPP with invasive characteristics Retrospective review of 12 patients 8 patients with traditional CPPs, 4 patients with variant CPPs yet invasive (patchy, local invasion) yet benign histology Only one subtotal resection in patient with variant Five year survival rate: 100% Summary: Stromal invasion may not be as useful a criterion of carcinoma as nuclear features and loss of architecture Gross total resection is the key in all cases Choroid Plexus Tumors: Significance of Stromal Invasion

75. Typical CPP Variant (Invasive) CPP: -Replacement of epithelium, -Invasion into surrounding brain From M Levy et al, Neurosurgery, 2001

76. CT often demonstrates punctate calcification MRI: –Isodense to brain on T1 imaging –Brightly enhancing lesions –Enlarged choroidal artery can be noted –CP carcinomas with necrosis, calcification, hemorrhage, homogeneous enhancement –CP papillomas with “mottled” appearance Choroid Plexus Tumors: Radiographic Features

77. Study by Krieger et al, Neurosurgical Focus, 2005 MR Spectroscopy analysis of 6 children with newly diagnosed intraventricular brain tumors Retrospectively, 3 with CP papilloma, 3 with CP carcinoma CP papilloma: –Significant peak of myoinositol (mI) (20.4 vs. 4.1, p<0.01) –Elevated mI/Cho and Glx/Cho ratios CP carcinoma: –Lack of mI elevation –Elevated Choline –Low NAA/Cho, Cr/Cho, mI/Cho ratios (significant) Choroid Plexus Tumors: MR Spectroscopy

78. CP Papilloma: Prominent mI Peak CP Carcinoma: Prominent Cho Peak From Krieger et al, Neurosurgical Focus, 2005

79. Hydrocephalus –Requirement for VP shunting ranges from 37% to 78% –Raimondi and Gutierrez recommend initial of shunting all patients with 3 rd or 4 th ventricular tumors –Hydrocephalus can resolve completely with gross total resection –High likelihood of VP shunt obstruction: Secondary to high protein, debris, blood Choroid Plexus Tumors: Treatment

80. Operative Treatment –Focus on exposure of feeding artery –Avoiding eloquent cortical regions –Third ventricular lesions: Approach is midline transcallosal –Fourth ventricular lesions: Approach is midline posterior fossa craniectomy –Emphasis on minimizing blood loss (papilloma versus carcinoma) Choroid Plexus Tumors: Treatment

81. CP Carcinomas: –GTR achieved in less than 50% of cases given hemorrhagic tumor, invasiveness –No definitive guideleines following surgery –Postoperative chemotherapy: Cyclophosphamide, etoposide, vincristine, platinum agent Low response rate (8 of 22 in one study) –Postoperative radiation therapy: One study: 5 year survival following GTR was 68% with subsequent XRT versus 16% without XRT Recommended even following GTR given high relapse rates Choroid Plexus Tumors: Adjuvant Treatment

82. CP Papillomas: –5 and 10 year survival: 81% and 77% –Mortality usually in younger patients (less than one year) –Up to 33% with significant morbidity –Postoperative subdural fluid collections may require subdural-peritoneal shunting CP Carcinomas: –5 and 10 year survival: 41% and 35% Most important prognostic factor is extent of surgical resection Choroid Plexus Tumors: Outcomes

83. References 1. Gupta N. Choroid Plexus tumors in children. Neurosurg Clin N AM. 14 (2003) 21-631 2. Levy M et al. Choroid Plexus Tumors in Children: Significance of Stromal Invasion. Neurosurgery 48: 303- 309, 2001 3. Krieger MD et al. Neurosurgical Focus. 18(6a):E4, 1-4, 2005 4. Ellenbogen RG et al. Tumors of the choroid plexus in children. Neurosurgery 25: 327-335, 1989 5. Wolff JE et al. Radiation therapy and survival in choroid plexus carcinoma. Lancet 1999; 353:2126 6. Wolff JE et al. Choroid Plexus Tumors. Br J Cancer. 2002;87:1086-1091

84. Thank You