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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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%)
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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
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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
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Summary
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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
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Selected References
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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.
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