Ch35 Syndromes involving tumours Flashcards
Which neurocutaneous syndrome is not inherited via an autosomal dominant patter?
Sturge-Weber and ataxia telangiectasia
What is the incidence of NF1?
1 in 3000
What is the incidence of NF2?
1 in 40 000
Gene locus for NF2
Ch22 (22q12.2)
Gene locus for Von Recklinghausen’s disease?
Ch17 (17q11.2)
Which neurocutaenous syndrome is associated with skeletal anomalies?
NF1
What is the gene product of the NF2 gene?
Schwannomin
What is the gene product of the NF1 gene?
neurofibromin
What proportion of NF2 cases are sporadic?
>50%
What are the histological differences between schwannoma and neuroma?
Schwannomas arise from schwann cells, which produce myelin. Neurofibromas consist of neurites (axons or dendrites of immature or developing neurons), Schwann’s cells, and fibroblasts within a collagenous or myxoid matrix. Schwannomas displace axons (centrifugal), neurofibromas are unencapsulated and engulf the nerve of origin (centripetal). Both contain Antoni A and B fibres, neurofibromas tend to have more Antoni B. In NF-1 2% develop into malignant peripheral nerve sheath tumours.
What is the diagnostic criteria for NF-1?
(Mnemonic NFBLOCA) - NIH 1988 criteria Two or more of the following: ≥ 6 café au lait spots, each ≥ 5 mm in greatest diameter in prepubertal individuals, or ≥ 15 mm in greatest diameter in postpubertal patients ≥ 2 neurofibromas of any type, or one plexiform neurofibroma (neurofibromas are usually not evident until age 10–15 yrs). May be painful Freckling (hyperpigmentation) in the axillary or intertriginous (inguinal) areas Optic glioma ≥ 2 Lisch nodules: pigmented iris hamartomas that appear as translucent yellow/brown elevations that tend to become more numerous with age Distinctive osseous abnormality, such as sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis (e.g. of tibia or radius) A first degree relative with NF1 by above criteria
Cause of hydrocephalus in NF-1?
Aqueduct stenosis
What does neurofibromin do?
Negative regulator of the Ras oncogene. Loss of neurofibromin function occurs in NF1 and results in elevation of growth-promoting signals.
What are the diagnostic criteria for NF-2?
(Mnemonic VFMSGPC) bilateral VS on imaging (MRI or CT) OR a first degree relative (parent, sibling, or offspring) with NF2 AND 1. unilateral VS OR 2. any TWO of the following: meningioma, schwannoma (including spinal root), glioma (includes astrocytoma, ependymoma), posterior subcapsular lens opacity, or cortical wedge cataract OR unilateral VS AND any TWO of the following: meningioma, schwannoma (including spinal root), glioma (includes astrocytoma, ependymoma), posterior subcapsular lens opacity, or cortical wedge cataract OR multiple meningiomas AND ONE of the following 1. unilateral VS OR 2. OR any TWO of the following: meningioma, schwannoma (including spinal root), glioma (includes astrocytoma, ependymoma), posterior subcapsular lens opacity, or cortical wedge cataract
What is the classical triad of tuberous sclerosis complex?
(Epiloia) Epilepsy Low inteillgence Adenoma sebaceum Full triad seen in <1/3 of cases
What is the inheritance pattern of Tuberous Sclerosis
Most cases are actually sporadic, otherwise autosomal dominant inheritance 2 genes identified TSC1 (Ch9) = Hamartin and TSC2 (Ch16) = Tuberin
What are the intracranial findings in Tuberous Sclerosis aka Bourneville’s disease?
Subependymal tubers (hamartomas) - almost always calcified SEGA (WHO grade 1, almost always at the foramen of Munro) - occur in 10% of TSC patients Cortical dysplasias Pachygyria / microgyria
How would you treat a SEGA in a patient with Tuberous sclerosis?
Resection if symptomatic Patients ≥ 3 years of age with increasing size of SEGA lesions have had sustained reduction of SEGA volume on everolimus (mTOR pathway inhibitor).
What is the diagnostic criteria for Sturge Weber syndrome?
Clinical criteria: 2 out of the following 3; Facial port-wine birth mark increased intra-ocular pressure leptomeningeal angiomatosis
How is sturge weber inherited?
Most cases are sporadic, somatic mutation in GNAQ gene on Ch9
What conditions are associated with neurocutaneous melanosis?
NF1
Sturge Weber
P-fossa cystic malformation (Dandy walker in 10%)
Intra spinal lipoma
Syringomyelia
Which brain tumour is most commonly associated with familial adenomatous polyposis? (BTP2)
Medulloblastoma
What are skin and CNS derived from embryologically?
Ectoderm
Which condition is associated with cutaneous schwannomas?
NF2 in 70%
Which condition is associated with Lisch nodules?
NF1 (not NF2!)
Which other conditions are associated with NF-1?
Mnemonic: SNAP SUM EKG Scwannomas Neurofibromas Aqueductal stenosis Phaeochromocytomas Syrinx UBOs Malignant tumours Exopthalmos Cognitive decline Kyphoscoliosos Gliomas
What are the clinical diagnostic criteria for tuberous sclerosis?
Need 2 major criteria or 1 major and 2 minor:
Major:
>2 Ash leaf macules (hypomelanotic) seen with a UV Woods lamp!
>2 angiofibromas
>1 ungal fibroma
Shagreen patch
Multiple retinal hamartomas
Cortical dysplasia
Subependymal nodules
SEGA
Cardiac rhabdomyoma
Lymphangioleiomyomatosis >1 angiomyolipomas
Minor: Confetti skin lesions Dental enamel pits Intraoral fibromas Renal cysts Non-retinal hamartomas
Mnemonic for Tuberous sclerosis features?
Mnemonic = USA ADORA CLASS C: Ungal fibromas Shahgreen patches Adenoma sebaceous / Angiofibromas Ash leaf macules Dental pits Oral fibromas Renal cysts Angiomylolipomas Cardiac rabdomyomas Lymphangioleiomyomatosis Achromic retinal patch Subependymoma SEGA Confetti skin lesions / calcified hamartomas
What is adenoma sebaceum?
Hamartomas of the skin
Where do calcifications occur intracerebrally in TSC?
Subependymal
What is the diagnosis of a contrast enhancing periventricular tumour in TSC?
SEGA enhance intensely
How do you resect SEGAs?
Interhemispheric Transcallosal
What are the diagnostic features of Sturge-Weber?
2 of:
Leptomeningeal angiomatosis
Ipsilateral port wine stain
Increased ocular pressures
(Localised cerebral atrophy and calcifications)
What are the classical features of Sturge-weber on skull xray?
Tram-track sign
What is the other name for Sturge Weber Syndrome?
Encephalotrigeminal angiomatosis
Where is the predilication for cortical calcification in Sturge-weber?
Occipital lobes
What features are associated with Sturge-Weber?
Mnemonic: EPIC GRAVE
Exopthalmos
Port wine stain
Iris Coloboma
Cortical atrophy / calcification
Glaucoma
Retinal angiomas
Atrophy of lobe
Oculomeningeal capillary haemangioma
Cerebral Venous malformation
Endocrinopathy (growth hormone deficiency)
What is the mutation in Tuberous Sclerosis?
TSC1 gene on Ch9q21 (Hamartin)
TSC2 gene on Ch16p13.3 (Tuberin)
How do you treat refractory seizures in tuberous sclerosis?
Lobectomy or hemispherectomy
What is the diagnosis?
Neurocutaneous melanosis
What is neurocutaneous melanosis?
A non-inherited phakomatosis that presents before 2 years of age with cutaneous and leptomeningeal benign or malignant melanomas. Due to a neuroectodermal defect originating from neural crest cells.
What % of patients with neurocutaneous melanosis develop hydrocephalus?
66%
What are the signal characteristics of melanin on MRI?
Bright T1 and Dark T2
What is Turcot syndrome?
Brain tumour polyposis syndrome 1 & 2 mutation of the APC - adenomatous polyposis syndrome gene)
Autosomal dominant
Type 1 is associated with gliomas
>90% have cafe-au-lait spots
Type 2 is associated with medulloblastomas
What is Li Fraumeni syndrome?
Autosomal dominant condition with P53 mutation causing medulloblastomas, embryonal tumorus and astrocytic tumours
What are these?
Lisch nodules (orange or brown iris hamartomas) associated with NF-1
What is the earliest indicator of tuberous sclerosis?
Ash leaf macules - these are ovoid hypopigmented patches that are more prominent with UV light (Wood’s lamp). 80% of patients with tuberous sclerosis have these present by one year of age.
May also have a white tuft of hair.
What is Waardenburg syndrome?
White tuft of hair
Iris heterochromia
Cutaneous depigmentation
Congenital sensorineural deafness
Characteristic facial features incl broad nasal root, lateral displacement of the mesial canthus
What is the triad of McCune-Albright?
Cafe au lait spots
Polyostotic fibrous dysplasia
Precocious puberty
What is Legius syndrome?
NF-1 like syndrome. Characterised by cafe-au-lait spots, axillary freckling, lipomas, macrocephaly and learning disability. Autosomal dominant.
Unlike NF-1 it does not have neurofibromas, bone abnormalities, lisch nodules, OPG and malignant PNST.
What is Cowden syndrome?
A mutation in PTEN resulting in benign hamartomas and malignant tumours (Breast ca, Endometrial ca, Thyroid ca etc). Characterised by palmar keratosis and facial trichilemmomas. Associated with Lhermite-Duclos (cerebellar gangliocytoma)
What do plexiform neurofibromas resemble?
Giant cafe au lait spots. They enlarge and become elevated with a bag of worms consistency.
Seen with NF-1
What is Gorlin syndrome?
Basal cell carcinoma syndrome. Multiple BCCs on the plantar surfaces (palms and soles)
What is the other term for a port wine stain?
Naevus flammeus (associated with sturge-weber, Klippel-Trenauny syndrome and VHL)
What is Klippel-Trenauny syndrome?
Port wine stain
Overgrowth of soft tissue
Venous abnormalities
What are the MEN syndromes?
MEN1 = MENIN gene mutation = Pituitary/Parathyroid/pancreatic islet cell tumours. Characterised by facial angiofibromas, collagenomas, lipomas, guttate hypopigmented macules.
MEN2A = RET gene mutation = (PAT) Parathyroid/Thyroid/Adrenal = lichen amyloidosis of the upper back
MEN2B = RET gene mutation = (TAG) Thyroid/Adrenal/GI ganglioneuromatosis = Marfanoid habitus with multiple mucosal neuromas
What condition are collagenomas associated with?
MEN1 (MENIN gene mutation)
What are trichilemmomas?
Proliferation of the root sheath of hair follicles appering as papules on the face. Associated with Cowden’s syndrome.
What is diagnostic of an ATRT?
SMARCB1 gene loss / INI1 protein loss
What mutation is found with pilocytic astrocytomas?
BRAF-KIAA 1549 gene fusion
What is the diagnosis?
ATRT
What are Ch6 monosomy and MYC gene amplifications associated with?
Ch6 monosomy = Low-risk medulloblastoma
MYC gene amplifications = High-risk medulloblastoma
What is associated with raised levels of beta-2-microglobulin?
Multiple myeloma and CLL
What is associated with raised levels of CA19.9?
Pancreatic cancers
What is associated with raised levels of CA125?
Ovarian cancer
What is associated with raised levels of calcitonin?
Medullary thyroid cancer
What is associated with raised levels of CEA?
Colorectal cancers
What are Verocay bodies?
A characteristic feature of Scwannomas (Antoni A pattern) they are parallel rows of nuclear atypia separated by regions of acellularity.
What type of rosettes are associated with ependymomas?
True ependymoma rosettes and perivascular pseudorosettes
What type of rosettes are associated with medulloblastomas, retinoblastoma and pineoblastomas?
Flexner wintersteiner rosettes
What are Negri bodies?
Eosinophilic cytoplasmic inclusions associated with Rabies
What immunostain is positive with chordomas?
Brachyury
What tumours are TTF-1 positive?
TTF-1 = thyroid transcription factor.
Positive with thyroid and lung metastases
What immunomarker is positive with central neurocytomas?
Synaptophysin
What condition is associated with breast ca, sarcoma and astrocytomas?
Li Fraumeni syndrome (P53 mutation)
What staining is associated with SEGAs?
S100.
Note: SEGAs arise from subependymal nodules that grow and are > 1cm. Calcification is common and show marked contrast enhancement.
Where do central neurocytomas arise from?
The septum pellucidum. Maximal safe resection is standard of care.
What is the incidence of an incidental pineal cyst on MRI?
1-4%. Imaging surveillance is recommended.
Which conditions are associated with AVMs?
HHT, Wyburn-Mason syndrome, Sturge-Weber syndrome
What are Rosenthal fibres?
Intracytoplasmic aggregates of GFAP (seen in Grade I ganglioglioma or Grade II pleomorphic xanthoastrocytoma, and Alexander’s disease (type of leukodystophy))
What are Hirano bodies?
Rode-like eosinophilic aggregates of ACTIN seen in Alzheimer’s disease and CJD
What are Herring bodies?
Neurosecretory bodies found in the posterior pituitary
What are pseudopalisades associated with?
GBM (note: real palisades are associated with Verocay bodies in Antoni A regions of schwannomas)
What are the phases of the cell cycle?
Prophase > Metaphase > Anaphase >Telophase > Cytokinesis > G1
What are the histological features of a PXA?
Cellular and nuclear pleomorphism
Spindled cells
Lipidized tumour cells
Multinucleated cells
Very low mitotic rate
Eosinophilic granular bodies
What are glomeruloid tufts?
Microvascular proliferations seen in GBM composed of multiple layers of endothelial cells surrounding vessels
How can you differentiate Flexner-Wintersteiner rosettes from Homer-Wright rosettes?
The central lumen contains neuropil with Homer-Wright rosettes
What are the features of tanycytic ependymomas of the spinal cord?
Highly fibrillated bipolar spindle cells.
What are the histological features of myxopapillary ependymomas?
Myxoid matrix with microcystic structures. Tumour cells are radially arranged around papillary vascular cores.
What are the histological features of cortical tubers?
Dystrophic neurons with balloon cells
What condition are ependymomas associated with?
NF2
What immunoreactivity is seen with choroid plexus carcinomas?
P53! Think Li Fraumeni
What are the two types of cafe au lait spots?
Coast of California - smooth edges
Coast of Maine - craggy edges (less common)
