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Genetic Syndromes with Central Nervous System Tumors Charmi Vijapura¹, Toshio Moritani¹, Bruno Policeni¹, Aristides A Capizzano¹, Yutaka Sato¹ ¹University of Iowa Hospitals and Clinics eEdE-51 Financial Disclosures The authors of this educational exhibit have no financial disclosures Purpose This review will focus on genetic syndromes and the neuroimaging of their CNS tumors. Discussion will include the genetics, molecular biology, diagnostic criteria, treatment options, screening and follow-up of these hereditary syndromes with intracranial manifestations. This Interactive exhibit will allow you to review each syndrome by CLICKING on the name below or CONTINUING FORWARD. There is an option of returning to the MAIN (this slide) at the beginning and end of each case: Von Hippel Lindau (VHL) Tuberous Sclerosis Neurofibromatosis Type 1 (NF1) Neurofibromatosis Type 2 (NF2) Familial Schwannomatosis Familial Clear Cell Meningioma Familial Retinoblastoma Ataxia Telangiectasia (AT) Li-Fraumeni Cowden Gorlin Turcot Multiple Endocrine Neoplasia Type 1 (MEN1) GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 3p25 Hemangioblastoma (CNS & Retina) MOLECULAR • VHL gene -> Von Hippel Lindau • Tumor suppressor gene • Involved in a critical pathway for adaptation cells to hypoxia by downregulating hypoxia-inducible transcription factor • Decreased protein levels induce cell proliferation and increased expression of angiogenic factors such as VEGF Endolymphatic Sac Tumor Renal Clear Cell Carcinoma Adrenal Pheochromocytoma Islet Cell Tumor Renal and Pancreatic Cysts INCIDENCE • 1 in 31,000 to 36,000 live births Return to MAIN CC: 20 y/o female with headache Axial T1 Axial T2 Axial POST CE Hemangioblastoma MRI: Cystic lesion with internal septation and enhancing nodule in the vermis and posterior to the 4th ventricle Further Imaging) CC: Female with history of VHL Sagittal Venous Spine Images with Ferumoxytol Contrast Axial Delay Axial Noncontrast CT Coronal T2 HASTE Axial Arterial Axial POST CE Sagittal POST CE Sagittal POST CE Axial Arterial CECT Renal Cell Carcinoma (Bilateral) + Pheochromocytoma + PNET + Hemangioblastomas MRI/CT: Right Kidney CT with delays demonstrates a heterogeneously enhancing mass in the posterior aspect of the right upper pole. Left Kidney MRI shows several complex cystic lesions with internal enhancement. Isodense right adrenal mass identified without washout. Pancreatic head has a early arterial enhancing lesion. Spine MRI: Multiple enhancing tumors in the spinal canal (most prominent in the cervical region) consistent with hemangioblastomas. Incidental note of left pancreatic tail cyst. Diagnostic Criteria Screening and Follow-up Known Positive Family Hx – presence of one: Single retinal or cerebellar hemangioblastoma RCC Pheochromocytoma Annual ophthalmologic evaluation and visual field testing starting around age 2 Negative Family Hx – 2 retinal or cerebellar hemangioblastomas Single hemangioblastoma and additional characteristic lesion. Treatment Hemangioblastomas Complete surgical resection Incomplete resection + external beam RT VEGF and PDGF pathway inhibitors (sunitinib and sorafinib) MRI of the brain and spine every 2 years starting in early adolescence Annual abdominal US starting at age 5 Abdominal CT or MRI starting at age 20 Frequent blood pressure monitoring and measurement of urinary catecholamine levels or plasma metanephrine levels every 1–2 years starting at age 2 What is the most common presenting feature in VHL patients? Hemangioblastoma, 60% of the time Return to MAIN GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosomes 9q31 and 16q13 • 70% cases sporadic • Wide variety of germline mutations Giant Cell Astrocytoma MOLECULAR • TSC1 -> Hamartin • TSC2 -> Tubulin • Tumor suppressor genes • Heterodimerize to inhibit mTOR pathway (mammalian target of rapamyacin) • Cell proliferation and growth through mRNA translation and ribosome synthesis INCIDENCE • 1 in 6,000 to 10,000 live births Ependymoma Bilateral Renal Angiomyolipomas Renal Cell Carcinoma (Childhood) Cardiac Rhabdomyoma Other CNS Abnormalities: Tubers Heterotopia CNS migration Psychomotor delay Seizures Return to MAIN CC: 17 y/o male with seizures and vomiting Right Kidney (Long) Axial T1 Axial T2 Coronal POST CE Axial GRADIENT Left Kidney (Long) Subependymal Giant Cell Astrocytoma + Angiomyolipomas MRI: Heterogeneously enhancing lesion at the left foramen of Monro with small mass effect on the septum pellucidum. Blooming artifact on gradient consistent with calcification. US: Multiple hyperechoic foci diffusely distributed in the renal parenchyma bilaterally consistent with angiomyolipomas. Diagnostic Criteria Screening and Follow-up Definite diagnosis: 2 major or 1 major and 2 minor criteria Probable diagnosis: 1 major and 1 minor criteria Possible diagnosis: 1 major or 2 minor criteria Funduscopic examination Major Criteria: Skin manifestation (facial angiofibroma, ungual fibroma, >3 hypomelanotic macules, shagreen patch) Brain and eye lesions (cortical tuber, subependymal nodules, subependymal giant cell astrocytoma, multiple retinal nodular hamartomas) Tumors in other organs (cardiac, rhabdomyoma, lymphangioleiomyomatosis, renal angiomyolipoma) Brain MR imaging Minor Criteria: Pits in dental enamel Rectal polyps Bone cysts Cerebral white matter migration abnormalities Gingival fibromas Nonrenal hamartomas Retinal achromic patches Confetti skin lesions Multiple renal cysts Renal US or CT Echocardiography/Electrocardiography Treatment SEGA Surgical resection Rapamycin can cause regression and prevention of epilepsy Where are SEGAs typically located and causes what complication? Foramen of Monroe, Hydrocephalus Return to GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 17q11.2 • Penetrance = 100% • ~50% new mutations Optic Glioma (Nerve and Chiasmatic) MOLECULAR Plexiform Neurofibroma • NF gene -> Neurofibromin • Negative regulator of RAS oncogene • Tumor suppressor gene • Inactivation causes cell growth and tumor development • Regulates neuroglial progenitor function Pheochromocytoma INCIDENCE Neurofibrosarcoma Glioblastoma Multiforme Pilocytic Astrocytoma Embryonal rhabdomyosrcoma Leukemia (chronic myelogenous) Malignant peripheral nerve sheath tumor Neuroblastoma GIST • 1 in 2,500 to 3,000 live births Return to MAIN CC: 33 y/o male with right facial and orbit deformity Axial T1 Axial T2 Axial POST CE Coronal POST CE Plexiform Neurofibroma MRI: Large infiltrative transspatial mass involving the right hemiface extending into the oral cavity, infratemporal fossa, stylomastoid foramen, masticator, carotid, parotid, and parapharygeal spaces. Right globe appears elongated shape and visualized as buphthalmos with proptosis. CC: (TWIN 1 & 2) 10 y/o males with daily headaches Twin #2 Axial T1 Axial FLAIR Axial POST CE Twin #1 Axial T1 Axial FLAIR Axial POST CE Glioblastoma Multiforme (TWINS) MRI (TWIN 1): Large enhancing right frontal mass with hemorrhage. There is significant surrounding vasogenic edema and probable invasion of the right frontal horn at the foramen of monro. MRI (TWIN 2): Large left frontal mass containing fluid centrally and peripheral soft tissue enhancement and nodularity. Mass appears to extend into the corpus callosum at the genu. There is diffuse leptomeningial enhancement and evidence of mass effect anteriorly. DISCUSSION: This case of twins highlights the familial aspect of GBM and NF1. The final histologic and genetic analysis for the tumors were very similar. Unfortunately, both twins died from their GBMs. CC: 13 y/o with right eye blindness Axial T1 Coronal T2 Coronal POST CE Optic Nerve Glioma MRI: Right optic nerve mass with with mildly hyperintense T2, isointense T1 and minimal contrast enhancement. Lesion extends from the posterior globe through the orbital apex without mass effect. CC: 16 y/o female with difficulty with peripheral vision than central Coronal T1 Coronal T2 Sagittal POST CE Axial POST CE Chiasmatic Glioma MRI: Irregular, lobulated mass in the suprasellar region with T1 isointense and T2 hyperintensity with central enhancement and peripheral nonenhancing rind. CC: 12 y/o female with seizures and headache Axial Noncon CT Axial FLAIR Axial FLAIR Coronal T2 Axial POST CE Follow-up: Acute ER visit Post Intervention Pilocytic Astrocytoma MRI: Increased FLAIR and enhancing mass lesion in the left medial temporal lobe. CT (after acute symptoms): Partially calcified and hemorrhagic mass which appears to extend into the left ventricle lumen. Moderate acute hydrocephalus. MRI (post intervention): Left frontoparietotemporal craniectomy with left temporal mass resection and hemorrhagic changes. Significant edematous changes are seen. CC: 43 y/o male with tiredness and confusion Axial Noncontrast CT Axial FLAIR Axial GRADIENT Axial DWI Coronal POST CE Epithelioid Hemangioepithelioma CT: Well circumscribed round hyperdense mass with focal hypodense areas. Surrounding edema extending along the optic radiations. MRI: Midline mass in the third ventricle with mixed signal. Significant low signal on gradient consistent with hemorrhage. Heterogeneous central enhancement and moderate hydrocephalus is seen. DISCUSSION: Rare vascular soft tissue tumor, both clinically and histologically. Only one prior case reported in association with NF1, a syndrome which has a higher risk of sarcoma and neoplasia. Diagnostic Criteria Screening and Follow-up Requires the presence of at least 2 of the following criteria > 6 Café-au- lait macules (>5 mm in children and >15 mm in adults) > 2 Cutaneous or subcutaneous neurofibromas or one plexiform neurofibroma Axillary or inguinal freckling Optic pathway glioma > 2 Lisch nodules (small elevated hamartomas of the iris) > 1 Distinctive osseous lesion (sphenoid wing dysplasia or thinning of long bone cortex) First-degree relative with NF1 Yearly physical exam Treatment Optic glioma Surgery RT (after age 5) Chemotherapy (carboplatin + vincristine) Plexiform Neurofibromas Tipifarnib (RAS inhibitor) Yearly ophthalmologic exam in early childhood ( up to age 5) Regular developmental assessment Routine blood pressure monitoring Appropriate monitoring by a specialist according to CNS, skeletal, or cardiovascular abnormalities What are the most common tumors in children with NF1? Optic nerve Gliomas (~15%) Return to MAIN GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 22q11 • 100% penetrance • >50% new mutations and negative family history Vestibular Schwannoma (Bilateral) MOLECULAR Meningioma Ependymoma Pilocytic Astrocytoma • NF2 Gene -> Merlin • Cytoskeleton organizing protein • Tumor suppressor protein • Involved in cell proliferation via the PAK/Rac signaling system • Cell membrane stability, motility, and intracellular adhesion INCIDENCE • 1 in 25,000 to 40,000 live births Return to MAIN CC: 15 y/o female right-sided hearing loss Axial T1 Axial T2 Axial T2 Coronal POST CE Axial POST CE Meningioma + Bilateral Vestibular Schwannoma MRI: Large right posterior horn intraventricular mass that is T1/T2 isointense mass and demonstrates avid enhancement. There is mild surrounding edema. Large right enhancing mass at the right cerebellopontine angle extending into the internal auditory canal. CC: 23 y/o female with decreased hearing Axial POST CE Coronal POST CE Axial POST CE Axial 3D CISS Coronal POST CE Vestibular Schwannoma + Ependymoma MRI: Enhancing lesion in the left cerebellopontine angle with extension into the left ICA. There is evidence of mass effect on the left pons with deformity of the fourth ventricle. Focus of enhancement in the right IAC. Multiple enhancing intramedullary lesions in the medulla and upper cervical cord. Diagnostic Criteria Screening and Follow-up Definite diagnosis if either condition is fulfilled 1) Bilateral vestibular schwannomas 2) 1st-degree relative with NF2 and either a) Unilateral vestibular schwannoma <30 years b) Any 2 of the following: meningioma, schwannoma, glioma, posterior subcapsular lens opacity or cerebral calcifications Probable diagnosis if either condition is fulfilled 1) Unilateral vestibular schwannoma at <30 years and at least one of the following: meningioma, schwannoma, glioma, posterior subcapsular lens opacity 2) Multiple meningiomas and either of the following: schwannoma, glioma, posterior subcapsular lens opacity Annual MRI starting at age 10 to at least age 40 Treatment Vestibular schwannoma Surgical resection (translabyrinthine or suboccipital retrosigmoid) Radiation therapy Stereotactic radiosurgery vs. External beam Frequent hearing and vision evaluation NF2-associated schwannomas are what World Health Organization grade? Grade 1 Vestibular schwannomas most commonly affect what cranial nerves? Cranial nerves VII (facial) and VIII (vestibulocochlear) Return to MAIN GENETICS Diagnostic Criteria • Germline mutation in SMARCB1 (aka INII) • Seen in 40-50% of familial cases • Tumor suppressor gene • MOLECULAR DIAGNOSIS • SMARCB1-associated schwannomatosis • Two or more pathologically proved schwannomas or meningiomas AND genetic studies of at least two tumors with loss of heterozygosity (LOH) for chromosome 22 and two different NF2 mutations; if there is a common SMARCB1 mutation • Pathologically proved schwannoma or meningioma AND germline SMARCB1 pathogenic mutation • Two or more non-intradermal schwannomas, one with pathological confirmation, including no bilateral vestibular schwannoma by MRI One pathologically confirmed schwannoma or intracranial meningioma AND affected first-degree relative Exclusion criteria: Patients with the following characteristics do not fulfill diagnosis for schwannomatosis • Germline pathogenic NF2 mutation • Fulfill diagnostic criteria for NF2 • First-degree relative with NF2 • Schwannomas in previous field of radiation therapy only Return to MAIN CC: 48 y/o with multiple lumps Axial T2 Axial T2 Axial POST CE Coronal POST CE Sagittal POST CE Axial POST CE Axial POST CE Multiple Schwannomas MRI: Hyperintense T2 and heterogenously enhancing masses involving the floor of the right middle cranial fossa extending into the right cavernous sinus. Additional multiple enhancing tumors are seen in the left carotid space and thoracolumbar spine. Intraabdominal mass is seen lateral to the right psoas muscles. MOLECULAR • Most common mutation is seen in the NF2 gene • Novel mutation in SMARCE1 • SWI/SNF DNA remodeling complex subunit gene Coronal T1 Coronal POST CE CC: 55 y/o male with persistent migraines, left facial numbness, and intermittent double vision Axial POST CE Coronal POST CE Clear Cell Meningiomas MRI: Hypointense and avidly enhancing masses adjacent to the bilateral cavernous sinuses. Additional enhancing mass at the pontomedullary junction compressing the medulla and extending into the hypoglossal canal with evidence of necrosis. Return to MAIN GENETICS • Autosomal Dominant • Gene locus on Chromosome 13q14 • 85-95% Penetrance, depending on type of mutation Imaging Manifestations Retinoblastoma (Bilateral) Osteosarcoma Soft Tissue Sarcoma MOLECULAR Melanoma • RB1 -> pRB protein • Cell cycle control, differentiation and apoptosis • Genomic stability Breast Cancer Leukemia INCIDENCE • 1 in 13,500 to 25,000 Return to MAIN CC: 14 month old found to have leukocoria by father. Mother with hx of unilateral retinoblastoma and enucleation at age 5. Coronal T1 Axial T1 Coronal T2 Axial POST CE Retinoblastoma MRI: Enhancing lesion involving the posterior segment of the right eye globe. Another small enhancing lesion is seen involving the posterior segment of the left eye globe adjacent to the optic nerve head. Normal bilateral optic nerves. CC: 42 y/o female with Hx germline retinoblastoma s/p RT prior to age 1 now with right upper eyelid tender mass for one month Axial T1 Coronal T2 Coronal POST CE Axial POST CE Coronal POST CE Lacrimal Gland Liposarcoma + Meningioma (2o to RT) MRI: Enhancing mass in the right lacrimal gland extending into the right foramen rotundum and inferior part of the right cavernous sinus and into the inferior temporal fossa through the right foramen ovale, consistent with perineural extension of the tumor. Small dural-based enhancing lesion posterior to the left sphenoid wing consistent with meningioma. CC: 30 y/o male with Hx of bilateral retinoblastoma s/p RT now worsening left vision Sagittal Noncon CT Axial T1 Coronal T2 Sagittal POST CE Axial Noncon CT High Grade Spindle Cell Sarcoma (2o to RT) CT: Soft tissue mass centered on the left sphenoid sinus with thinning of the upper anterior skull base and erosion of the left medial orbital wall. MRI: Enhancing mass centered in the left orbital apex extending to the posterior left ethmoid sinus and left cavernous sinus through the inferior orbital fissure and foramen rotundum. Screening and Follow-up Treatment Clinical examination monthly from birth to age 3 months Retinoblastoma Enucleation Cryotherapy Laser, systemic, or local chemotherapy Radiation therapy using episcleral plaques External beam radiotherapy (last resort) Examination with anesthesia every 2 months to age 7 month Examination with anesthesia every 3 months to age 18 months Examination with anesthesia every 6 months to age 3 years Examination with anesthesia annually to age 7 Trilateral retinoblastoma refers to the combination of retinoblastoma and what tumor? Pineoblastoma Return to MAIN GENETICS • Autosomal recessive • Gene locus on Chromosome 11q2223 MOLECULAR • ATM -> Ataxia telangiectasia mutated • Protein kinase • DNA damage response and associated cell-cycle checkpoint regulation INCIDENCE • 1 in 40,000 to 100,000 live births Imaging Manifestations Pilocytic Astrocytoma Medulloblastoma Glioblastoma Multiforme Lymphoma/Leukemia Lung Cancer Breast Cancer Ovarian Cancer Stomach Cancer Other CNS Abnormalities: Vascular telangiectasias Cerebellar atrophy Return to MAIN CC: 18 y/o male with difficulty walking Axial FLAIR Coronal POST CE Axial SWI Axial T2 Meningioma + Microhemorrhages + Cerebellar Atrophy MRI: Small dural-based lesion in the right frontal lobe with increased FLAIR and contrast enhancement consistent with meningioma. Numerous foci of blooming artifact throughout the cerebral hemispheres from telangiectasias and cerebellar atrophy. Diagnostic Criteria Treatment Progressive cerebellar dysfunction between ages one and four years. Presenting as: • Gait and truncal ataxia • Head tilting • Slurred speech • Oculomotor apraxia and uneven (interrupted or “bumpy”) tracking across a visual field More sensitive to ionizing radiation Desferrioxamine – increase genomic stability Neurologic manifestation Beta-adrenergic blockers Lymphoma Chemotherapy Lung infections Antibiotics Screening and Follow-up Physical, Occupational and Speech therapy What does MR Spectroscopy show in AT? Increased choline signal in the cerebellum Return to MAIN GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 17p13 • 70% of affected families have germline missense mutation High-Grade Astrocytoma MOLECULAR Medulloblastoma • TP53 -> Tumor protein p53 • Tumor suppressor gene • Controls cell cycle arrest, apoptosis and DNA damage repair • Mutations in CHEK2 (Checkpoint kinase gene) seen in TP-53 negative families • Product stabilizes p53 INCIDENCE Supratentorial Primitive Neuroectodermal Tumor Choroid Plexus Carcinoma Osteosarcoma Soft Tissue Sarcoma Breast Cancer Melanoma Adrenocortical Carcinoma Leukemia • Rare, no consensus Return to MAIN CC: 19 y/o with increasing seizure frequency Axial FLAIR Axial T2 Axial POST CE Oligodendroglioma MRI: Focus of T2/FLAIR hyperintensity and slightly decreased contrast enhancement images in the anterior left temporal lobe. CC: 26 y/o female with aphasia Axial FLAIR Axial POST CE Axial DWI Axial ADC Mapping Glioblastoma Multiforme with Oligodendroglioma Component MRI: Enhancing lesion in the left frontal lobe with large peritumoral edema and left to right midline shift. There is evidence of necrosis and diffusion restriction. Compression of the left anterior horn is seen with dilation of the right posterior horn. DISCUSSION: This patient had a strong family history of cancer including a father with melanoma/sarcoma/carcinoma, brother with rhabdomyosarcoma, and sister with adrenal Diagnostic Criteria Screening and Follow-up Li–Fraumeni syndrome is diagnosed if the following three criteria are met: US of the abdomen/pelvis every 3–4 months 1. Patient has been diagnosed with a sarcoma at a young age (below 45) 2. First-degree relative has been diagnosed with any cancer at a young age (below 45) 3. Another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age. Treatment Medulloblastomas, Choroid plexus carcinoma and PNET Surgery Chemotherapy Radiation Complete urinalysis every 3–4 months Blood work (measurement of ESR, LDH, BHCG, AFP, 17-OH progesterone, testosterone, androsterodione, and DHEAS levels) every 4 months Monthly breast self-examination (starting at age 18), biannual clinical breast examination Annual mammography starting at age 20–25 Annual total-body MRI What are the 2 most common frequent cancers reported with LFS? Premenopausal breast cancer and sarcoma Return to MAIN GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 10q2223 Dysplastic Cerebellar Gangliocytoma MOLECULAR • PTEN gene -> Phosphatase and TENsin homolog protein • Cell cycle arrest and/or apoptosis • Size control of neurons Breast Cancer Thyroid (Follicular Adenoma, Follicular and Papillary Carcinoma) Endometrial Carcinoma INCIDENCE • 1 in 250,000 live births Return to MAIN CC: 21 y/o female with headaches, nausea and vomiting Axial Noncontrast CT Axial T2 Sagittal T2 Axial T2 Dysplastic Cerebellar Gangliocytoma MRI: Midline left cerebellar hemisphere demonstrates enlarged folds of folia with resultant mass effect on adjacent tissue below level of fourth ventricle. There is symmetric ventriculomegaly of the bilateral lateral ventricles, third ventricle, and fourth ventricle. CC: 32 y/o male with history of Juvenile polyposis and newly diagnosed esophageal cancer, eval for thyroid and brain lesions. Axial T1 Axial T2 Axial POST CE Rt Thyroid LONG Rt Thyroid LONG Rt Thyroid TRANS Rt Thyroid TRANS Dysplastic Cerebellar Gangliocytoma + Follicular Carcinoma MRI: Ill-defined T1 hypointense and T2 hyperintense lesion in the right cerebellar hemisphere with mild mass effect on the fourth ventricle and without enhancement. US: Isoechoic large mid right thyroid nodule with thin surrounding halo and increased vascularity. CC: 54 y/o with word finding difficulty and poor concentration Axial T2 Axial T2 Axial DWI Axial POST CE Coronal POST CE Gliosarcoma + Lhermitte-Duclos Disease MRI: Heterogenous peripherally enhancing left temporal lobe lesion with necrotic central component. There is evidence of significant vasogenic edema with left to right mildline shift and left uncal herniation. Increased signal on diffusion weighted image reflecting tumor cellularity. Folial thickening in the left cerebellum consistent with LDD. Screening and Follow-up Treatment Yearly physical exam at age 18 or 5-10 years before the age of the first family member with a cancer diagnosis Lhermitte-Duclos Surgery (to relieve obstructive hydrocephalus but will not improved cerebellar symptoms) Shunting Yearly mammogram and breast MR imaging starting at age 30-35 Yearly US starting at age 18 In the setting of sepsis and acute deterioration, what can mimic LDD? Cerebellitis Return to MAIN GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 11q13 • Age-related penetrance (~78% at age 50) Anterior Pituitary Gland Adenoma (50% microadenomas) MOLECULAR • MEN1 -> Menin protein • Tumor suppressor gene • Gene transcription, cell proliferation, apoptosis, and genomic stability Parathyroid Gland Adenoma Pancreatic Neuroendocrine Tumors (gastrinoma> insulinoma> glucagonoma) Adrenal Cortical Tumor Carcinoid Lipomatous tumor INCIDENCE Collagenoma • Rare, no consensus Facial Angiofibroma Return to MAIN CC: 39 y/o female with galactorrhea and hypercalcemia Coronal T1 Coronal T2 Sagittal POST CE Tc-99m Sestamibi Pituitary Microadenoma + Parathyroid Adenoma MRI: Pituitary gland lesion with minimal enhancement in the posterior-mid aspect slightly to the left. These is slight upward convexity of the pituitary gland. No cavernous sinus extension. Scintigraphy: Intense focus of uptake at the inferior aspect of the right thyroid which persists on delayed images. Diagnostic Criteria Screening and Follow-up TWO of the below three endocrine tumors occur in a patient: Screening starting at age 5–10 years, including measurement of fasting glucose, calcium, PTH, insulin, prolactin, and IGF1 levels • • • Anterior pituitary adenoma Parathyroid gland adenoma Pancreatic neuroendocrine tumor Treatment Pituitary tumor Prolactinoma - Bromocriptine or cabergoline Somatotrophinomas - Octreotide or lenreotide Transsphenoidal tumor removal with RT Parathyroid adenoma/Hyperparathyroidism Subtotal or total parathyroidectomy with an open bilateral neck exploration Transcervical thymectomy Pancreatic islet cell tumor Surgical removal Annual pancreatic US Pancreatic and pituitary MR imaging every 3–5 years Yearly abdominal CT or MR imaging Yearly head MRI What tumor of the MEN1 trifecta is usually the first manifestation? Parathyroid tumor (87%) Return to MAIN GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 5 Medulloblastoma MOLECULAR • PMS2 -> Postmeiotic segragation increased • MLH1 -> MutL homolog 1 • MSH2 -> MutS homolog 2 • DNA mismatch repair (MMR) genes • Disruption of the WNT signaling pathway INCIDENCE Glioblastoma Multiforme Anaplastic Astrocytoma Ependymoma Colon Cancer/Multiple Colonic Polyps Screening and Follow-up Routine MRI for symptoms • Rare, no consensus Diagnostic Criteria Primary CNS tumor and evidence of colorectal polyposis Treatment Medulloblastoma/GBM surgical resection radiation therapy chemotherapy Return to MAIN GENETICS Imaging Manifestations • Autosomal dominant • Gene locus on Chromosome 9q Desmoplastic Medulloblastoma MOLECULAR Multiple Basal Cell Carcinomas • PTCH -> Drosophila Melanogaster Patched Gene • Encodes a transmembrane receptor for secreted ligand sonic hedgehog (SHH) • Essential for cerebellar development Screening and Follow-up INCIDENCE • 1 in 50,000 live births Diagnostic Criteria Diagnosis presence of 2 or more major criteria or 1 major criteria plus 2 or more minor criteria Major Criteria: Calcification of the falx cerebri, Bifid or fused ribs, Jaw cysts, Palmar/plantar pits, 1st degree relative with the same syndrome Minor Criteria: Medulloblastoma, Ovarian fibroma, Macrocephaly, Congenital facial or skeletal abnormalities Neuro exam every every 6 months, then annually from age 3-7 Panorex annually from age 8 onward Routine MRI Treatment Medulloblastoma Surgical resection Radiation (reduced dose and targeted because risk for 2o basal cell carcinomas) Small molecule inhibitors of the SHH pathway Cyclopamine Return to MAIN Summary Return to MAIN Syndrome Gene CNS Tumors Other Malignancies Treatments Ataxia Telangiectasia ATM Medulloblastoma, GBM, Pilocytic astrocytoma Leukemia/Lymphoma, Breast, Gastric Desferrioxamine, B-blocker Cowden PTEN Dysplastic cerebellar astrocytoma Breast and thyroid cancer Surgery, Shunting Familial Retinoblastoma RB1 Retinoblastoma Osteosarcoma Enucleation, cryotherapy, chemotherapy, RT Gorlin PTCH Desmoplastic Medulloblastoma Basal cell carcinoma Surgery, RT reduced dose, SHH inhibitor Li-Fraumeni TP53 Astrocytoma, Choroid plexus carcinoma, Medulloblastoma, PNET Breast cancer, Leukemia, adrenocortical carcinoma, Bone/Soft tissue sarcomas Surgery, RT, chemotherapy MEN MEN1 Pituitary Microadenoma Parathyroid adenoma, Pancreatic neuroendocrine tumor Bromocriptine, cabergoline, octreotide, lenreotide, RT NF1 NF1 Optic/Chiasmatic Glioma, Plexiform Neurofibroma, Pilocytic astrocytoma Leukemia, Pheo, Rhabdomyosarcoma, Surgery, RT, chemotherapy, Tipifarnib NF2 NF2 Vestibular Schwannoma, Meningioma None Surgical resection, RT Tuberous Sclerosis TSC1/TSC2 Subependymal giant cell astrocytoma Cardial Rhabdomyoma, Renal Angiomyolipoma Surgery, Rapamycin Turcot hMLH1, hPSM2, APC Medulloblastoma, GBM, Astrocytoma, Ependymoma Colon cancer Surgery, RT, chemotherapy VHL VHL Hemangioblastoma RCC, Pheo, Endolymphatic sac tumor VEGF and PDGF pathway inhibitors, Surgery, RT Return to MAIN Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Hottinger, Andreas F., and Yasmin Khakoo. "Update on the management of familial central nervous system tumor syndromes." Current neurology and neuroscience reports 7.3 (2007): 200-207. Farrell, Christopher J., and Scott R. Plotkin. "Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von HippelLindau, and other syndromes." Neurologic clinics 25.4 (2007): 925-946. Turcot, Jacques, Jean-Paul Després, and François St. Pierre. "Malignant tumors of the central nervous system associated with familial polyposis of the colon." Diseases of the Colon & Rectum 2.5 (1959): 465-468. Monsalve, Johanna, et al. "Imaging of Cancer Predisposition Syndromes in Children 1." Radiographics 31.1 (2011): 263-280. Reis, C., et al. "Epithelioid hemangioendothelioma and multiple thoraco-lumbar lateral meningoceles: two rare pathological entities in a patient with NF-1." Neuroradiology 47.2 (2005): 165-169. Marsh, Deborah J., and Roberto T. Zori. "Genetic insights into familial cancers–update and recent discoveries." Cancer letters 181.2 (2002): 125-164. Hottinger, Andreas F., and Yasmin Khakoo. "Neurooncology of familial cancer syndromes." Journal of child neurology 24.12 (2009): 1526-1535. Garber, Judy E., and Kenneth Offit. "Hereditary cancer predisposition syndromes." Journal of Clinical Oncology 23.2 (2005): 276292. Trump, D., et al. "Clinical studies of multiple endocrine neoplasia type 1 (MEN1)." Qjm 89.9 (1996): 653-670. Hottinger, Andreas F., Yasmin Khakoo, and Lauren E. Abrey. "Familial Central Nervous System Tumor Syndromes." Current Cancer Therapy Reviews 2.4 (2006): 281-291. Lin, D. D. M., et al. "Cerebral abnormalities in adults with ataxia-telangiectasia." American Journal of Neuroradiology 35.1 (2014): 119-123. Raffalli-Ebezant, Helen, et al. "Pediatric intracranial clear cell meningioma associated with a germline mutation of SMARCE1: a novel case." Child's Nervous System (2012): 1-7. Kleihues, Paul, and Webster K. Cavenee. Pathology and genetics of tumours of the nervous system. International Agency for Research on Cancer, 2000. Peterson, R. D., et al. "Cancer susceptibility in ataxia-telangiectasia." Leukemia 6 (1991): 8-13. Reis, Rui M., et al. "Genetic profile of gliosarcomas." The American journal of pathology 156.2 (2000): 425-432. Tinat, Julie, et al. "2009 version of the Chompret criteria for Li Fraumeni syndrome." Journal of Clinical Oncology 27.26 (2009): e108-e109. THANK YOU!